ID Name Pathway EC_code Organism TaxID KEGG_pathway Pubmed_ID Description_of_Rate_limiting_role Comment_from_IntEnz Office_name RL00001 Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (UDP-GlcNAc-2-epimerase/ManAc kinase) sialic acid biosynthesis 5.1.3.14/2.7.1.60 Human 9606 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530# 15987957,16550921,15748884,14972325, Hereditary inclusion body myopathy (HIBM) is an autosomal recessive neuromuscular disorder associated with mutations in uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE)/N-acetylmannosamine (ManNAc) kinase (MNK), the bifunctional and rate-limiting enzyme of sialic acid biosynthesis[15987957]#GNE catalyzes the rate-limiting step in the sialic acid biosynthesis and MNK catalyzes the next step[16550921]#Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis[14972325]#The bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) is essential for early embryonic development and catalyzes the rate limiting step in sialic acid biosynthesis[15748884]# The enzyme hydrolyses the product to UDP and N-acetyl-D-mannosamine. UDP-N-acetylglucosamine 2-epimerase RL00002 pyruvate dehydrogenase complex tricarboxylic acid cycle 1.2.4.1/2.3.1.12/1.8.1.4 Human 9606 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine biosynthesis:map00290#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 10583428,10720420,10635003, In the same model, we evaluated pyruvate dehydrogenase (PDH), the rate limiting enzyme of glucose oxidation, in peripheral blood mononuclear cells[10583428]#Pyruvate dehydrogenase is a rate-limiting enzyme for pyruvate entry into the tricarboxylic acid cycle; its catalytic activity influences both pyruvate oxidation and lactate production[10635003]#The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation[10720420]# A multimer (24-mer or 60-mer, depending on the source) of this enzyme forms the core of the pyruvate dehydrogenase multienzyme complex, and binds tightly both EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively acetylated by EC 1.2.4.1, and the only observed direction catalysed by EC 2.3.1.12 is that where the acetyl group is passed to coenzyme A. dihydrolipoyllysine-residue acetyltransferase RL00005 cystathionine-beta-synthase the transsulfuration pathway 4.2.1.22 Human 9606 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271#Human Diseases:Neurodegenerative Diseases:Huntington's disease:map05040# 15642325, We examined the presence of the gene for cystathionine-beta-synthase (CBS), the rate limiting enzyme that converts homocysteine to cystathionine in the transsulfuration pathway, in human lens epithelial (HLE) B3 cells using PCR with primers designed based on the sequence of human liver CBS (Forward 5'-CCA CAC TGC CCC GGC AAA AT-3'; Reverse 5'-CTG GCA ATG CCC GTG ATG GT-3')[15642325]# A pyridoxal-phosphate protein. A multifunctional enzyme: catalyses beta-replacement reactions between L-serine, L-cysteine, cysteine thioethers, or some other beta-substituted alpha-L-amino acids, and a variety of mercaptans. cystathionine beta-synthase RL00011 Beta-secretase generation of the amyloid beta-peptide (Abeta) in Alzheimer disease 3.4.23.46 Human 9606 Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010# 15987683,16306400, Beta-secretase [beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the beta-amyloid (Abeta) peptide involved in the pathogenesis of Alzheimer's disease (AD)[16306400]#Beta-secretase (BACE1) is the rate-limiting protease for the generation of the amyloid beta-peptide (Abeta) in Alzheimer disease[15987683]# Suggested to be the major "beta-secretase" responsible for the cleavage of the beta-amyloid precursor protein to form the amyloidogenic beta-peptide that is implicated in the pathology of Alzheimer's disease. In peptidase family A1 but is atypical in containing a C-terminal membrane-spanning domain. memapsin 2 RL00015 Choline-phosphate cytidylyltransferase membrane phospholipid synthesis 2.7.7.15 Human 9606 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 3367156,11029581, Elevated PME could be secondary to a metabolic block at the rate-limiting enzyme in membrane phospholipid synthesis, which is cytidine triphosphate (CTP): phosphocholine (or phosphoethanolamine) cytidyltransferase (EC 2.7.7.15)[3367156]#The activity of membrane-bound CTP:phosphocholine cytidylyltransferase, the rate-limiting enzyme, was increased by 47 +/- 4% in cholesterol-enriched cells whereas its activity was unchanged in lathosterol-enriched cells[11029581]# choline-phosphate cytidylyltransferase RL00016 phosphoethanolamine cytidylyltransferase phosphatidylethanolamine synthesis 2.7.7.14 Human 9606 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 10752579, In contrast, the activity of phosphoethanolamine cytidylyltransferase (PECT), the rate-limiting enzyme of phosphatidylethanolamine synthesis, was significantly and markedly decreased by 35%-78% in the cerebellar, frontal, and occipital cortices of patients with FA but was normal in SCA-1[10752579]# ethanolamine-phosphate cytidylyltransferase RL00022 uroporphyrinogen synthase porphyrin synthesis 2.5.1.61 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 9065797,16886091,10546563,8023693,9460994,11953837,10787385,4067519, The observations may be explained by the known pH-dependency of the activity of porphobilinogen deaminase (PBGD) and are in agreement with the assumption that PBGD constitutes a rate-limiting step in the synthesis of PpIX from ALA[9065797]#The latter activation energy was within the error limits similar to that for the activity of the enzyme porphobilinogen deaminase, suggesting that this enzyme might represent a rate-limiting step for PpIX production in living tissue[10546563]#Two mechanisms may explain the results: enhancement of the efficiency of the rate-limiting enzyme porphobilinogen deaminase by folic acid or interference of folic acid with the transport of ALA and MAL to and into the cells synthesizing porphyrins in the tissues[16886091]#All cases of acute intermittent porphyria (AIP) are believed to be caused by a mutation in the gene encoding for porphobilinogen deaminase, a rate-limiting enzyme in the haem synthetic pathway[8023693]#Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase[10787385]#In the present study we focused on the role of the rate-limiting enzyme porphobilinogen deaminase in glioma C6 cell activity, differentiation and sub-cellular distribution[11953837]#These observations of an associated response of PBGD and PPIX imply that PBGD may be a rate-limiting determinant for the efficacy of delta-ALA-induced photosensitization when used in photodynamic therapy[9460994]#The conversion of exogenous ALA into porphyrins decreases with increasing concentrations of ALA from 0.1 to 2.0 mmol/l, whereas porphobilinogen accumulates, thus reflecting the rate limiting function of uroporphyrinogen synthase, which is not influenced by glucose[4067519]# The enzyme works by stepwise addition of pyrrolylmethyl groups until a hexapyrrole is present at the active centre. The terminal tetrapyrrole is then hydrolysed to yield the product, leaving a cysteine-bound dipyrrole on which assembly continues. In the presence of a second enzyme, EC 4.2.1.75 uroporphyrinogen-III synthase, which is often called cosynthase, the product is cyclized to form uroporphyrinogen-III. If EC 4.2.1.75 is absent, the hydroxymethylbilane cyclizes spontaneously to form uroporphyrinogen I. hydroxymethylbilane synthase RL00023 acetylcholinesterase acylation with certain substrates precedes general acid-base catalysis 3.1.1.7 Human 9606 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 1820094, Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions[1820094]# Acts on a variety of acetic esters; also catalyses transacetylations. acetylcholinesterase RL00024 butyrylcholinesterase hydrolysis of the positively charged oxoester benzoylcholine ( BzCh )/termination of cholinergic signaling at neuromuscular junctions 3.1.1.8 Human 9606 1820094, Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions[1820094]# Acts on a variety of choline esters and a few other compounds. cholinesterase RL00025 urokinase cleavage of the preactivation peptide from the NH2 terminus of native plasminogen( NH2-terminal glutamic acid ) 3.4.21.73 Human 9606 Cellular Processes:Immune System:Complement and coagulation cascades:map04610# 1150667,7639718,7046788, Stage 1 is maximally enhanced (75-fold) at either 0.0025 M epsilon-aminocaproic acid or 0.025 M lysine and occurs 4 times more rapidly than Stage 2, which becomes the rate-limiting step at these concentrations[1150667]#Bound plasminogen is rate-limiting for cell-surface-mediated activation of plasminogen by urokinase[7639718]#In the catalyzed hydrolysis of ZAlaONp, in the absence of acetamidine or ethylamine, the acylation step (k2) is rate limiting all over the pH range from 3 to 8[7046788]# Formed from the inactive precursor by action of plasmin or plasma kallikrein. Differs in structure from t-plasminogen activator (EC 3.4.21.68), and does not bind to fibrin. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.31 and EC 3.4.99.26 u-plasminogen activator RL00029 myosin light chain kinase initiation of myosin light chain phosphorylation 2.7.11.18 Human 9606 Cellular Processes:Cell Motility:Regulation of actin cytoskeleton:map04810#Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Cellular Processes:Cell Communication:Focal adhesion:map04510# 2678154,9612207,3337223, It appears that the rate of conversion of myosin light chain kinase from an inactive to an active enzyme may be a significant rate limiting step for the initiation of myosin light chain phosphorylation[2678154]#Even more surprising was that the myosin heavy chain (MHC) isoform (SM-B) generally said to be associated with the higher shortening velocity disappeared from the cell, while the content of the key rate-limiting regulating enzyme, myosin light chain kinase (MLCK), increased 30-fold[9612207]#Comparison of the rate constants indicates that latch-bridge detachment is the rate-limiting step[3337223]# Requires Ca2+ and calmodulin for activity. The 20-kDa light chain from smooth muscle myosin is phosphorylated more rapidly than any other acceptor, but light chains from other myosins and myosin itself can act as acceptors, but more slowly. myosin-light-chain kinase RL00033 beta hydroxysteroid dehydrogenase/isomerase sex steroid production from pregnenolone 1.1.1.145/5.3.3.1 Human 9606 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 12782399,239964, Hydroxyflutamide a specific androgen receptor (AR) antagonist, and cyproterone acetate or trilostane, both inhibitors of 3 beta-hydroxysteroid dehydrogenase/delta 4,5 isomerase, the rate-limiting enzyme for the conversion of DHEA to sex steroids, did not affect the ability of DHEA to downregulate GnRH gene expression[12782399]#Since isomerization appeared not to be the rate-limiting step of the overall reaction, measurement of activity of delta5-3beta-hydroxysteroid dehydrogenase was related to the amount of delta4-3-oxosteroid produced from the corresponding delta5-3beta-hydroxysteroid[239964]# May be at least three distinct enzymes. steroid Delta-isomerase RL00045 Renin renin-angiotensin system 3.4.23.15 Human 9606 Cellular Processes:Endocrine System:Renin - angiotensin system:map04614# 6205842,14728059,3334166,16990260,16787263,15731500, Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin[6205842]#Renin is the enzyme that catalyzes the first and rate-limiting step of RAS, the cleavage of angiotensinogen to angiotensin I (A-I)[14728059]#Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II[16990260]#Renin catalyzes the first and rate-limiting step of the RAS and, unlike ACE, has a high specificity for its endogenous protein substrate[3334166]#Renin, released by the kidney, circulates and acts-in the rate-limiting step of angiotensin II (Ang II) production-to convert angiotensinogen to inactive angiotensin I (Ang I)[15731500]#As the rate-limiting enzyme in ANGII production, renin inhibitors have been pursued as an additional class of anti-hypertensives[16787263]# Formed from prorenin in plasma and kidney. In peptidase family A1 (pepsin A family). renin RL00047 HMG CoA synthase mevalonate pathway/ketogenesis 2.3.3.10 Human 9606 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Lipid Metabolism:Synthesis and degradation of ketone bodies:map00072#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 16101500, The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase)[16101500]# hydroxymethylglutaryl-CoA synthase RL00048 17-hydroxylase-17,20-lyase androgen biosynthesis 1.14.99.9 Human 9606 Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 2019257,10352919, Therefore, we determined the effects of estrogen treatment at midgestation and removal of estrogen action near term on the specific activity of the rate-limiting enzymes delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 17-hydroxylase-17,20-lyase (17 alpha-OHase)[2019257]#The most likely cause of the excessive androgen secretion by both glands seems to be abnormal regulation (dysregulation) of the 17-hydroxylase and 17,20-lyase activities of P-450c17, the rate-limiting step in androgen biosynthesis[10352919]# Requires NAD(P)H and P-450. steroid 17alpha-monooxygenase RL00049 glutathione s transferase arsenic biotransformation 2.5.1.18 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 15761769, GSTO1, a member of the glutathione S-transferase superfamily omega, has recently been shown to be identical to the rate-limiting enzyme, monomethyl arsenous (MMA(V)) reductase which catalyzes methylarsonate (MMA(V)) to methylarsenous acid (MMA(III)) during arsenic biotransformation[15761769]# A group of enzymes of broad specificity. R may be an aliphatic, aromatic or heterocyclic group; X may be a sulfate, nitrile or halide group. Also catalyses the addition of aliphatic epoxides and arene oxides to glutathione, the reduction of polyol nitrate by glutathione to polyol and nitrile, certain isomerization reactions and disulfide interchange. glutathione transferase RL00058 choline acetyl transferase synthesis of the neurotransmitter acetylcholine ( ACh ) 2.3.1.6 Human 9606 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 566752, Effect of sodium chloride on changing the rate-limiting step in the human placental choline acetyltransferase reaction[566752]# Propanoyl-CoA can act, more slowly, in place of acetyl-CoA. choline O-acetyltransferase RL00061 l myo inositol phosphate synthase conversion of D-glucose 6-phosphate to L-myo-inositol 1-phosphate in the inositol biosynthetic pathway 5.5.1.4 Human 9606 Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 16221686, DHAP as well as glyceraldehyde 3-phosphate and oxaloacetate inhibited activity of both yeast and human myo-inositol-3 phosphate synthase, the rate-limiting enzyme in de novo inositol biosynthesis[16221686]# Requires NAD+, which dehydrogenates the -CHOH- group to -CO- at C-5 of the glucose 6-phosphate, making C-6 into an active methylene, able to condense with the -CHO at C-1. Finally, the enzyme-bound NADH reconverts C-5 into the -CHOH- form. inositol-3-phosphate synthase RL00062 aldehyde dehydrogenase acetaldehyde metabolism 1.2.1.3 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:1,2-Dichloroethane degradation:map00631#Metabolism:Xenobiotics Biodegradation and Metabolism:3-Chloroacrylic acid degradation:map00641#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Biosynthesis of Secondary Metabolites:Limonene and pinene degradation:map00903#Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Ascorbate and aldarate metabolism:map00053#Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410# 7910607,9228057,16878979, Both the rat native enzyme and the E487K mutant oxidized chloroacetaldehyde twice as fast as acetaldehyde, indicating that the rate-limiting step was not hydride transfer or coenzyme dissociation but depended upon nucleophilic attack[7910607]#The basis for the change in the rate-limiting step appears to be related to NAD(+) binding[16878979]#The rate-limiting step remained deacylation for the E399H/D mutants when either aliphatic or aromatic aldehydes were used as substrates[9228057]# Wide specificity, including oxidation of D-glucuronolactone to D-glucarate. aldehyde dehydrogenase (NAD+) RL00063 sn glycerol phosphate acyl transferase 2.3.1.15 Human 9606 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 8387510, Further analysis of the glycerol 3-phosphate pathway showed that the rate-limiting enzyme activities for diacylglycerol conversion to triacylglycerol, diacylglycerol acyltransferase, and phosphatidylcholine, CTP:phosphocholine cytidylyltransferase, increased 2-3-fold and decreased approximately 40%, respectively, during Caco-2 differentiation[8387510]# Acyl-[acyl-carrier protein] can also act as acyl donor. The enzyme acts only on derivatives of fatty acids of chain length above C10 glycerol-3-phosphate O-acyltransferase RL00066 glycerol phosphate dehydrogenase glycerol phosphate shuttle 1.1.99.5 Human 9606 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 8682323, Mitochondrial glycerol phosphate dehydrogenase (mtGPD) is the rate-limiting enzyme in the glycerol phosphate shuttle, which is thought to play an important role in cells that require an active glycolytic pathway[8682323]# glycerol-3-phosphate dehydrogenase RL00067 acyl coA : cholesterol acyltransferase cholesterol esterification 2.3.1.26 Human 9606 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120# 8820097, In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT)[8820097]# The animal enzyme is highly specific for transfer of acyl groups with a single cis double bond that is nine carbon atoms distant from the carboxy group. sterol O-acyltransferase RL00069 hydroxy delta steroid dehydrogenase the sex steroid hormone biosynthesis pathway 1.1.1.145 Human 9606 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 8574339, We investigated the first two steps of the bile acid biosynthesis pathway by assaying the activities of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in this pathway, and 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase, and by measuring the concentrations of 7 alpha-hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one in liver specimens from ten patients with cholesterol gallstones and ten gallstone-free controls[8574339]# Acts on 3beta-hydroxyandrost-5-en-17-one to form androst-4-ene-3,17-dione and on 3beta-hydroxypregn-5-en-20-one to form progesterone. 3beta-hydroxy-Delta5-steroid dehydrogenase RL00070 phosphatidylinositol phosphate kinase PA biosynthesis 2.7.1.68 Human 9606 Cellular Processes:Cell Motility:Regulation of actin cytoskeleton:map04810#Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562# 9381980,15277528, In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess[9381980]#Phosphatidylinositol 4-phosphate 5-kinase (PIP5K) catalyzes the rate-limiting step in the production of phosphatidylinositol 4,5-bisphosphate (PIP(2)), a signaling phospholipid that contributes to actin dynamics[15277528]# This enzyme can also phosphorylate PtdIns3P in the 4-position, and PtdIns, PtdIns3P and PtdIns(3,4)P2 in the 5-position in vitro, but to a lesser extent. The last of these reactions occurs in vivo and is physiologically relevant. Three different isoforms are known. 1-phosphatidylinositol-4-phosphate 5-kinase RL00071 methionine adenosyl transferase methionine metabolism 2.5.1.6 Human 9606 Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271# 16413417, Because methionine adenosyl transferase (MAT) is the rate-limiting enzyme of the pathway, we examined the expression of a lung epithelial isoform of MAT 2A in hyperoxia[16413417]# methionine adenosyltransferase RL00073 medium chain acyl coA dehydrogenase medium-chain fatty acid beta-oxidation 1.3.99.2 Human 9606 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 8941110,9177236, In contrast, the activity and steady-state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or post-translational levels in the hypertrophied but nonfailing ventricle[8941110]#Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level[9177236]# A flavoprotein; forms, with another flavoprotein ('electron-transferring flavoproteins') and EC 1.5.5.1 electron-transferring-flavoprotein dehydrogenase, a system reducing ubiquinone and other acceptors. butyryl-CoA dehydrogenase RL00074 acyl coA dehydrogenase long-chain fatty acid beta-oxidation 1.3.99.13 Human 9606 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 12716879, Although the rate-limiting step in the inactivation of the other acyl-CoA dehydrogenases can involve the abstraction of a proton at C-4, this is not the case with glutaryl-CoA dehydrogenase[12716879]# A flavoprotein (FAD); forms with another flavoprotein ('electron-transferring flavoprotein') and EC 1.5.5.1 a system reducing ubiquinone and other acceptors. Not identical with EC 1.3.99.2 (butyryl-CoA dehydrogenase), EC 1.3.99.3 (acyl-CoA dehydrogenase), EC 1.3.99.10 (isovaleryl-CoA dehydrogenase) or EC 1.3.99.12 (2-methylacyl-CoA dehydrogenase). long-chain-acyl-CoA dehydrogenase RL00076 acetyl-CoA : lyso PAF acetyltransferase Platelet activating factor biosynthesis 2.3.1.67 Human 9606 Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565# 1693077,2848827, Theophylline and MIX lacked any inhibitory effect on acetyl-CoA: lyso-PAF acetyltransferase activity, which is the rate-limiting step for PAF biosynthesis in PMN[1693077]#Thrombin-stimulated endothelial cells produce platelet-activating factor (PAF) in a dose-dependent manner: the activation of a Ca2+-dependent lyso-PAF acetyltransferase is the rate-limiting step in this process[2848827]# 1-alkylglycerophosphocholine O-acetyltransferase RL00078 carbamoyl phosphate synthase the de novo UTP biosynthetic pathway 6.3.5.5 Human 9606 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 4361297,15326225,12678497, Cytidine (10(-3) M) inhibited synthesis through the salvage pathway, but did not significantly alter induction of carbamyl phosphate synthetase II, the rate-limiting enzyme for the de novo pathway[4361297]#The rate-limiting step in de novo pyrimidine nucleotide synthesis is catalyzed by the carbamoyl phosphate synthetase II (CPSase) domain of CAD[15326225]#Recent studies demonstrate that CAD, a rate-limiting enzyme in the de novo synthesis of pyrimidines, is regulated through reversible phosphorylation, Myc-dependent transcriptional changes and caspase-mediated degradation[12678497]# The product carbamoyl phosphate is an intermediate in the biosynthesis of arginine and the pyrimidine nucleotides [4]. The enzyme from Escherichia coli has three separate active sites, which are connected by a molecular tunnel that is almost 100 A in length [8]. The amidotransferase domain within the small subunit of the enzyme hydrolyses glutamine to ammonia via a thioester intermediate. The ammonia migrates through the interior of the protein, where it reacts with carboxy phosphate to produce the carbamate intermediate. The carboxy-phosphate intermediate is formed by the phosphorylation of bicarbonate by ATP at a site contained within the N-terminal half of the large subunit. The carbamate intermediate is transported through the interior of the protein to a second site within the C-terminal half of the large subunit, where it is phosphorylated by another ATP to yield the final product, carbamoyl phosphate [6]. carbamoyl-phosphate synthase (glutamine-hydrolysing) RL00080 dihydro orotate dehydrogenase de novo synthesis of pyrimidines and progression of the cell cycle in different cell lines,mainly activated T lymphocytes 1.3.3.1 Human 9606 Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 16556484,6761622,17046731,16163233, OBJECTIVES:: Life-threatening toxic side-effects following 5-FU exposure have been related to deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in its catabolism[17046731]#DPYD encodes dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme in a three-step metabolic pathway involved in degradation of the pyrimidine bases uracil and thymine[16556484]#Through the use of pharmacogenetic studies, interindividual variability in response (efficacy and toxicity) to 5-fluorouracil (5-FU) chemotherapy has been linked to the rate-limiting enzyme in the drug's catabolic pathway, known as dihydropyrimidine dehydrogenase (DPD)[16163233]# A flavoprotein (FAD, FMN). Ferricyanide can act as acceptor. dihydroorotate oxidase RL00081 phosphoribosyl pyrophosphate synthetase purine biosynthesis 2.7.6.1 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030# 217337, The product of the enzyme 5-phosphoribosyl-1-pyrophosphate (PPriboseP) synthetase is a substrate for purine, pyrimidine, and pyridine biosynthesis and may be rate limiting for purine biosynthesis[217337]# dATP can also act as donor. ribose-phosphate diphosphokinase RL00086 arachidonyl coA synthetase esterification of arachidonic acid by many human cells 6.2.1.3 Human 9606 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 15051725, Taken together, these results support the hypotheses that ACSs are rate-limiting for fatty acid internalization and that ACS2 enhances neurite outgrowth by promoting PUFA internalization[15051725]# Acts on a wide range of long-chain saturated and unsaturated fatty acids, but the enzymes from different tissues show some variation in specificity. The liver enzyme acts on acids from C6 to C20; that from brain shows high activity up to C24. long-chain-fatty-acid---CoA ligase RL00087 alcohol dehydrogenase alcohol oxidation 1.1.1.1 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350#Metabolism:Xenobiotics Biodegradation and Metabolism:3-Chloroacrylic acid degradation:map00641#Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Metabolism:Xenobiotics Biodegradation and Metabolism:1- and 2-Methylnaphthalene degradation:map00624#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 11303599,3067025,12489977, The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs)[11303599]#Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate[3067025]#The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1 g/L[12489977]# A zinc protein. Acts on primary or secondary alcohols or hemi-acetals; the animal, but not the yeast, enzyme acts also on cyclic secondary alcohols. alcohol dehydrogenase RL00094 fatty acid synthase fatty acid biosynthetic pathway 2.3.1.85 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 16054091, Work in this issue of Cell Metabolism (Najjar at al., 2005) suggests a new mechanism for the inhibition of the rate-limiting enzyme in liver, fatty acid synthase.[16054091]# The animal enzyme is a multi-functional protein catalysing the reactions of EC 2.3.1.38 [acyl-carrier-protein] S-acetyltransferase, EC 2.3.1.39 [acyl-carrier-protein] S-malonyltransferase, EC 2.3.1.41 3-oxoacyl-[acyl-carrier-protein] synthase, EC 1.1.1.100 3-oxoacyl-[acyl-carrier-protein] reductase, EC 4.2.1.61 3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase, EC 1.3.1.10 enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) and EC 3.1.2.14 oleoyl-[acyl-carrier-protein] hydrolase. fatty-acid synthase RL00096 adenine phosphoribosyl transferase AMP formation and subsequently the formation of ADP and ATP 2.4.2.7 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 2154328,6327016, Relative to normal brain the tumors had significantly lower ATP and GTP levels, essentially normal pool sizes of purine nucleosides and bases, unchanged activities of the salvage enzymes hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and adenosine kinase (659, 456, and 98 nmol/h/mg protein, respectively) and 4-fold higher activities of IMP dehydrogenase (11.6 nmol/h/mg protein); the latter is the rate limiting enzyme for guanylate de novo synthesis[2154328]#The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# 5-Amino-4-imidazolecarboxamide can replace adenine. adenine phosphoribosyltransferase RL00097 PI kinase phosphatidylcholine synthesis 2.7.1.137 Human 9606 Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Genetic Information Processing:Folding, Sorting and Degradation:Regulation of autophagy:map04140# 9292730, Moreover, transient expression of dominant-negative and wild-type phosphatidylinositol 3-OH kinase (PI 3-kinase) subunits, as well as application of specific inhibitors, demonstrates that PI 3-kinase is an essential and rate-limiting messenger in this signaling pathway[9292730]# One mammalian isoform is known. phosphatidylinositol 3-kinase RL00477 5'-nucleotidase transformation of AMP to adenosine 3.1.3.5 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Nicotinate and nicotinamide metabolism:map00760#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 10766785,9315889, In H9c2 cells, in which 5'-nucleotidase activity was rate-limiting, only cN-II overexpression accelerated inosine and hypoxanthine formation[10766785]#AMP, ADP, and ATP were all rapidly converted to adenosine, with a T1/2 for ATP conversion to adenosine of approximately 200 msec, and the last step in this pathway (transformation of AMP to adenosine by 5'-nucleotidase) seems to be the rate-limiting step[9315889]# Wide specificity for 5'-nucleotides. 5'-nucleotidase RL00554 Delta6 desaturase (D6D) highly unsaturated fatty acid (HUFA) synthesis 1.14.19.3 Rat 10116 Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591# 16106047, Delta6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets[16106047]# An iron protein. The rat liver enzyme is an enzyme system involving cytochrome b5 and EC 1.6.2.2, cytochrome-b5 reductase. linoleoyl-CoA desaturase RL00555 Delta6 desaturase (D6D) highly unsaturated fatty acid (HUFA) synthesis 1.14.19.3 Human 9606 Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591# 12538078, Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis[12538078]# An iron protein. The rat liver enzyme is an enzyme system involving cytochrome b5 and EC 1.6.2.2, cytochrome-b5 reductase. linoleoyl-CoA desaturase RL00102 gamma glutamyl transferase glutathione synthesis 2.3.2.2 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Metabolism of Other Amino Acids:Cyanoamino acid metabolism:map00460#Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 15006645, The increase in activity of both GPX and GST corresponded with increased transcription of these enzymes, as well as the rate-limiting enzyme in GSH synthesis, gamma-glutamyl transferase[15006645]# gamma-glutamyltransferase RL00108 sulfatase estrogen synthesis (the sulfatase was the rate-limiting enzyme in estrogen synthesis yet in vitro studies found that it was the aromatase) 3.1.6.2 Human 9606 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150# 6233132, The sulfatase was found to be rate limiting at concentrations of DS below 2 microM and the aromatase was found to be rate limiting at higher concentrations[6233132]# Also acts on some related steryl sulfates. steryl-sulfatase RL00109 spermidine synthase formation of the spermine precursor spermidine from putrescine 2.5.1.16 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271# 2775206, The rate-limiting enzymes in polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), are negatively regulated by the polyamines spermidine and spermine[2775206]# This enzyme is not identical with EC 2.5.1.22, spermine synthase. The mammalian enzyme is highly specific but the bacterial enzyme can use other acceptors and can synthesize spermine. spermidine synthase RL00111 5'-nucleotidase transformation of AMP to adenosine 3.1.3.5 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Nicotinate and nicotinamide metabolism:map00760#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 10766785,15748706, In H9c2 cells, in which 5'-nucleotidase activity was rate-limiting, only cN-II overexpression accelerated inosine and hypoxanthine formation[10766785]#Here, we determined the activities and mRNA levels of deoxynucleoside kinases (dNK) and 5'-nucleotidases (5'-NT) controlling the rate-limiting step in intracellular phosphorylation of NRTIs in cell models representing adipose, muscle tissue and peripheral blood cells using specific assays and Taqman RT-PCR[15748706]# Wide specificity for 5'-nucleotides. 5'-nucleotidase RL00115 malate dehydrogenase the NADH shuttle that produces ATP in glucose metabolism 1.1.1.37 Human 9606 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glyoxylate and dicarboxylate metabolism:map00630#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Energy Metabolism:Carbon fixation:map00710# 131232, The normal activity of glucose-6-phosphate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), which supply NADPH for the reduction of acetyl-CoA to fatty acids, would suggest that the change in lipogenesis is of moderate degree, thereb) affecting only the most rate-limiting enzyme, ATP citrate-lyase[131232]# Also oxidizes some other 2-hydroxydicarboxylic acids. malate dehydrogenase RL00128 uridine diphosphoglucose dehydrogenase synthesis of HA 1.1.1.22 Human 9606 Metabolism:Carbohydrate Metabolism:Ascorbate and aldarate metabolism:map00053#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040#Metabolism:Carbohydrate Metabolism:Nucleotide sugars metabolism:map00520# 8471533, Uridine diphosphoglucose dehydrogenase (UDPGD) activity is the irreversible, rate-limiting step in the production of UDP-glucuronate, an essential monosaccharide in the synthesis of HA[8471533]# Also acts on UDP-2-deoxyglucose. UDP-glucose 6-dehydrogenase RL00129 thymidine kinase synthesis of dTTP/the salvage pathway of nucleotide metabolism 2.7.1.21 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 9816259, 5'-AdThd is a thymidine analogue that at low concentrations (<30 micrometer) can increase thymidine kinase activity, which is the rate-limiting enzyme for activation of IdUrd[9816259]# Deoxyuridine can also act as acceptor, and dGTP can act as a donor. The deoxypyrimidine kinase complex induced by Herpes simplex virus catalyses this reaction as well as those of EC 2.7.1.114 (AMP---thymidine kinase), EC 2.7.1.118 (ADP---thymidine kinase) and EC 2.7.4.9 (dTMP-kinase). thymidine kinase RL00131 squalene epoxidase sterol biosynthesis/cholesterol biogenesis 1.14.99.7 Human 9606 Metabolism:Biosynthesis of Secondary Metabolites:Terpenoid biosynthesis:map00900#Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 9286711, Squalene epoxidase (EC 1.14.99.7) catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway[9286711]# A flavoprotein (FAD). This enzyme, together with EC 5.4.99.7 lanosterol synthase, was formerly known as squalene oxidocyclase. squalene monooxygenase RL00135 pyruvoyl tetrahydropterin synthase synthesizing BH4/the synthesis of human tetrahydrobiopterin 4.2.3.12 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 11022034,11778454,11744995,9788822, Neither the mRNA expression of the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the activities of either GTP cyclohydrolase I or 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de novo synthesis pathway, were altered by ascorbate[11022034]#Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase[11778454]#In addition, we also measured 6-pyruvoyl tetrahydropterin synthase (PTPS) activities, the rate-limiting enzyme in synthesizing BH4, in pregnant women at the 30th gestational week and non-pregnant women[11744995]#Although GTPCH is believed to be the rate-limiting step, control of endothelial PTPS expression by cytokines may play an important role in regulating BH4-dependent nitric oxide production in the vascular system[9788822]# Catalyses triphosphate elimination and an intramolecular redox reaction in the presence of Mg2+. It has been identified in human liver. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 3.5.4.16 (GTP cyclohydrolase I) [3]. 6-pyruvoyltetrahydropterin synthase RL00136 pyruvate kinase glycolysis 2.7.1.40 Human 9606 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Energy Metabolism:Carbon fixation:map00710# 2820531,15028426, The effect of F-2,6-P2 on the rate-limiting enzymes of glycolysis, ie, hexokinase, phosphofructokinase (PFK), and pyruvate kinase, has also been examined[2820531]#We determined activity and protein expression of the three rate-limiting glycolytic enzymes phosphofructo kinase (PFK), pyruvate kinase (PK) and hexokinase (HXK) in a cytoplasmic fraction of homogenates of placentae obtained from IUGR and appropriate for gestational age (AGA) pregnancies[15028426]# UTP, GTP, CTP, ITP and dATP can also act as donors. Also phosphorylates hydroxylamine and fluoride in the presence of CO2. pyruvate kinase RL00137 prolyl cis trans isomerase protein-folding 5.2.1.8 Human 9606 Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Genetic Information Processing:Folding, Sorting and Degradation:Ubiquitin mediated proteolysis:map04120# 2656691, Peptidyl prolyl cis-trans-isomerase increased the refolding rate to 0.083 min-1, indicating that cis-trans-isomerization is the rate-limiting step, despite the interruptions in the triple helix[2656691]# The first type of this enzyme found [1] proved to be the protein cyclophilin, which binds the immunosuppressant cyclosporin A. Other distinct families of the enzyme exist, one being FK-506 binding proteins (FKBP) and another that includes parvulin from Escherichia coli. The three families are structurally unrelated and can be distinguished by being inhibited by cyclosporin A, FK-506 and 5-hydroxy-1,4-naphthoquinone, respectively. peptidylprolyl isomerase RL00148 leukotriene a4 hydrolase biosynthesis of leukotriene B4 3.3.2.6 Human 9606 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 1311589,6329309,12865451, These results were explained after a comparison of the rates of synthesis of these 5-lipoxygenase metabolites in the presence and absence of added arachidonic acid which led to the conclusion that leukotriene A hydrolase, the enzyme catalysing the formation of LTB4, was saturated with substrate and rate-limiting for LTB4 synthesis during A23187 stimulation[1311589]#Since delta 6-trans-leukotriene B4 represents the nonenzymatic decomposition of leukotriene A4, we suggest that one of the rate-limiting steps in the synthesis of leukotriene B4 is the leukotriene A4 hydrolase[6329309]#Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis of leukotriene B4 (LTB4), a potent inflammatory mediator[12865451]# This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.2.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [3]. leukotriene-A4 hydrolase RL00150 Glucose-6-phosphatase gluconeogenesis 3.1.3.9 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 9506766, Glucose-6-phosphatase (G6Pase) catalyzes the rate-limiting step of gluconeogenesis, and hepatic G6Pase activity is increased in diabetes[9506766]# Wide distribution in animal tissues. Also catalyses potent transphosphorylations from carbamoyl phosphate, hexose phosphates, diphosphate, phosphoenolpyruvate and nucleoside di- and triphosphates, to D-glucose, D-mannose, 3-methyl-D-glucose or 2-deoxy-D-glucose [cf. EC 2.7.1.62 (phosphoramidate---hexose phosphotransferase), EC 2.7.1.79 (diphosphate---glycerol phosphotransferase) and EC 3.9.1.1 (phosphoamidase)]. glucose-6-phosphatase RL00151 Glucokinase glucose metabolis 2.7.1.2 Human 9606 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Human Diseases:Metabolic Disorders:Maturity onset diabetes of the young:map04950#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 12941786,16186394,15009676, Glucokinase (GCK) is a key regulatory enzyme in the pancreatic beta-cell and catalyzes the rate-limiting step for beta-cell glucose metabolism[12941786]#As the rate-limiting controller of glucose metabolism, glucokinase represents the primary beta-cell "glucose sensor." Inactivation of both glucokinase (GK) alleles results in permanent neonatal diabetes; inactivation of a single allele causes maturity-onset diabetes of the young type 2 (MODY-2)[16186394]#This enzyme is considered to be the true glucose sensor because it catalyses the rate-limiting step of glucose catabolism its activity being regulated by interaction with glucokinase regulatory protein, that functions as a metabolic sensor[15009676]# A group of enzymes found in invertebrates and microorganisms that are highly specific for glucose. glucokinase RL00156 dipeptidyl peptidase the hydrolysis of the alanine substrates 3.4.14.5 Human 9606 12223360, Moreover, as estimated from the residual peptide structure and confirmed by exogenous peptidase supplementation, dipeptidyl peptidase IV and dipeptidyl carboxypeptidase I were identified as the rate-limiting enzymes in the digestive breakdown of these peptides[12223360]# A homodimer. An integral protein of the plasma membrane of lymphocytes and other mammalian cells, in peptidase family S9 (prolyl oligopeptidase family). The reaction is similar to that of the unrelated EC 3.4.14.11 Xaa-Pro dipeptidyl-peptidase of lactococci dipeptidyl-peptidase IV RL00157 deoxycytidine kinase metabolism of gemcitabin 2.7.1.74 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 15803490,16463058,12054682,16421443,11888330, In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials.Although it was synthesized early in the 1980s, the development of clofarabine was stalled until 1993, when, through efforts at The University of Texas M[15803490]#Deficiency in deoxycytidine kinase (dCK), the rate-limiting activating enzyme, has been reported in a number of in vitro models as well as in various clinical situations[16463058]#Clofarabine is phosphorylated intracellularly by human deoxycytidine kinase (dCK) to the 5'-monophosphate, which is the rate-limiting step in activation of the prodrug[16421443]#The rate-limiting enzyme in this pathway is deoxycytidine kinase (dCK)[12054682]#The rate-limiting step in the formation of triphosphate is conversion of F-ara-A to its monophosphate, which is catalyzed by deoxycytidine kinase[11888330]# Cytosine arabinoside can act as acceptor; all natural nucleoside triphosphates (except dCTP) can act as donors. deoxycytidine kinase RL00159 cytochrome c oxidase oxidative phosphorylation 1.9.3.1 Human 9606 Metabolism:Energy Metabolism:Oxidative phosphorylation:map00190# 12874793, COX is the only electron transport chain complex to display isoforms, consistent with its suggested rate-limiting role[12874793]# A cytochrome of the a type containing copper. The reduction of O2 to water is accompanied by the extrusion of four protons from the intramitochondrial compartment. Several bacteria appear to contain analogous oxidases. cytochrome-c oxidase RL00161 cis retinol dehydrogenase biosynthesis of 9-cis-retinoic acid 1.1.1.105 Human 9606 11377978, The 11-cis retinol dehydrogenase (11-cis-RoDH) enzyme catalyzes the oxidation of cis-retinols to their respective retinals, a rate limiting step in the formation of retinoic acids[11377978]# retinol dehydrogenase RL00162 choline kinase biosynthesis of phosphatidylcholine 2.7.1.32 Human 9606 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 2153442, Perfusion with the phospholipid precursors ethanolamine or choline (2 mM) indicates that the cytidylyltransferase enzymes are rate limiting for both pathways[2153442]# Ethanolamine and its methyl and ethyl derivatives can also act as acceptors. choline kinase RL00163 carboxyl ester lipase severe pancreatic exocrine dysfunction 3.1.1.3 Human 9606 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561# 3678753, 14CO2 was expired more rapidly than 13CO2, suggesting that hydrolysis of the substrate may also be rate limiting in healthy volunteers[3678753]# The pancreatic enzyme acts only on an ester-water interface; the outer ester links are preferentially hydrolysed. triacylglycerol lipase RL00164 arginine glycine transamidinase creatine synthesis 2.1.4.1 Human 9606 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330# 7419715, We administered intravenous arginine to six patients and six controls to study in vivo inhibition by high ornithine concentrations of arginine-glycine transamidinase, the rate-limiting enzyme in creatine synthesis[7419715]# Canavanine can act instead of arginine. glycine amidinotransferase RL00171 xanthine oxidoreductase purine catabolism 1.17.1.4 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 12502743, Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism occurring in most cell types[12502743]# Acts on a variety of purines and aldehydes, including hypoxanthine. The enzyme from eukaryotes contains [2Fe-2S], FAD and a molybdenum centre. The animal enzyme can be interconverted to EC 1.17.3.2, xanthine oxidase (the oxidase form). That from liver exists in vivo mainly in the dehydrogenase form, but can be converted into EC 1.17.3.2 by storage at -20 _degree_C, by treatment with proteolytic agents or organic solvents, or by thiol reagents such as Cu2+, N-ethylmaleimide or 4-mercuribenzoate. The effect of thiol reagents can be reversed by thiols such as 1,4-dithioerythritol. This enzyme can also be converted into EC 1.17.3.2 by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide. In other animal tissues, the enzyme exists almost entirely as EC 1.17.3.2, but can be converted into the dehydrogenase form by 1,4-dithioerythritol. xanthine dehydrogenase RL00172 xanthine oxidase nucleic acid degradation/purine catabolism 1.17.3.2 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 1353938,187329, In cancer cells, the up-regulation of guanylate biosynthesis is amplified by the concurrent decrease in activities of the catabolic enzymes, nucleotidase, nucleoside phosphorylase, and the rate-limiting purine catabolic enzyme, xanthine oxidase[1353938]#The behavior of the rate-limiting enzyme of purine catabolism, xanthine oxidase (EC 1.2.3.2); was examined in normal liver, in 17 hepatomas of different growth rates, and in rapidly growing differentiating and regenerating liver[187329]# An iron-molybdenum flavoprotein (FAD) containing [2Fe-2S] centres. Also oxidizes hypoxanthine, some other purines and pterins, and aldehydes (i.e. possesses the activity of EC 1.2.3.1, aldehyde oxidase). Under some conditions the product is mainly superoxide rather than peroxide: RH + H2O + 2 O2 = ROH + 2 O2.- + 2 H+. The enzyme from animal tissues can be converted into EC 1.17.1.4, xanthine dehydrogenase. That from liver exists in vivo mainly as the dehydrogenase form, but can be converted into the oxidase form by storage at -20 _degree_C, by treatment with proteolytic enzymes or with organic solvents, or by thiol reagents such as Cu2+, N-ethylmaleimide or 4-mercuribenzoate. The effect of thiol reagents can be reversed by thiols such as 1,4-dithioerythritol. EC 1.17.1.4 can also be converted into this enzyme by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide. The Micrococcus enzyme can use ferredoxin as acceptor. xanthine oxidase RL00174 tyrosine aminotransferase catabolic pathway of tyrosine 2.6.1.5 Human 9606 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400#Metabolism:Amino Acid Metabolism:Phenylalanine metabolism:map00360#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271#Metabolism:Biosynthesis of Secondary Metabolites:Novobiocin biosynthesis:map00401#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 6123525,2870018, The liver enzyme tyrosine aminotransferase (TAT; EC 2.6.1.5) catalyzes the rate-limiting step in the catabolic pathway of tyrosine[2870018]#These results suggest that tyrosine aminotransferase is the rate limiting enzyme in the catabolism of tyrosine in premature infants.[6123525]# A pyridoxal-phosphate protein. L-Phenylalanine can act instead of L-tyrosine. The mitochondrial enzyme may be identical with EC 2.6.1.1 (aspartate transaminase). The three isoenzymic forms are interconverted by EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain). The enzyme can also catalyse the final step in the methionine-salvage pathway of Klebsiella pneumoniae [8]. tyrosine transaminase RL00176 tissue type plasminogen activator the fibrinolytic cascade 3.4.21.68 Human 9606 Cellular Processes:Immune System:Complement and coagulation cascades:map04610# 10957661,8999865,8349826,12945771, Fibrinolysis was assessed through measurement of the activities of the rate limiting fibrinolytic activator, tissue plasminogen activator, and its inhibitor plasminogen activator inhibitor-1 with amidolytic methods[10957661]#For example, tissue type plasminogen activator (t-PA), a trypsin-like enzyme that catalyzes the rate-limiting step of the endogenous fibrinolytic cascade, has only one known substrate in vivo, a single peptide bond (Arg561-Val562) in the proenzyme plasminogen[8999865]#The data are consistent with a mechanism for glycosylasparaginase involving rapid formation of a tetrahedral structure upon substrate binding, and a rate-limiting breakdown of the tetrahedral structure to a covalent beta-aspartyl-enzyme intermediate that is dependent on the electronic properties of the substituent group and on the degree of protonation of the leaving group in the transition state by a general acid[12945771]#Tissue-type plasminogen activator (t-PA) is a plasma serine protease that catalyzes the initial and rate-limiting step in the fibrinolytic cascade[8349826]# A peptidase of family S1 (trypsin family) from a wide variety of mammalian tissues, especially endothelial cells. Secreted as a single chain precursor which is cleaved to a two-chain form by plasmin. Activity is considerably enhanced by fibrin. Formerly included in EC 3.4.21.31 and EC 3.4.99.26 t-plasminogen activator RL00177 thrombin formation of fibrin 3.4.21.5 Human 9606 Environmental Information Processing:Signaling Molecules and Interaction:Neuroactive ligand-receptor interaction:map04080#Cellular Processes:Cell Motility:Regulation of actin cytoskeleton:map04810#Cellular Processes:Immune System:Complement and coagulation cascades:map04610# 6743305,10543954,12389649, It is suggested that at 37 degrees C the processes of thrombin binding to the receptor, of receptor modification and of cellular response are immediately coupled with one another and that the rate-limiting step is the binding of thrombin to the receptor.[6743305]#Finally, kinetic modeling demonstrated that acylation is the rate-limiting step in thrombin inhibition by PAI-1 (k approximately 10(-3) s(-1)) and this kinetic block is alleviated by the introduction of the tPA-VR1 into thrombin (k>1 s(-1))[10543954]#The objective of this study was to determine whether there was evidence of in vivo generation of thrombin, the rate-limiting enzyme responsible for the formation of fibrin[12389649]# Formed from prothrombin. More selective than trypsin and plasmin. In peptidase family S1 (trypsin family). thrombin RL00179 retinal dehydrogenase the metabolism of retinal to retinoic acid 1.2.1.36 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830# 16763553, The tissue RA level is maintained through a cascade of metabolic reactions where retinal dehydrogenases (RALDHs) catalyze the terminal reaction of RA biosynthesis from retinal, a rate-limiting step[16763553]# A metalloflavoprotein (FAD). Acts on both the 11-trans- and 13-cis-forms of retinal. retinal dehydrogenase RL00180 pyruvate dehydrogenase acetyl coenzyme A synthesis/synthesis of acetylcholine 1.2.4.1 Human 9606 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine biosynthesis:map00290#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 10759582, This uptake rate corresponds to a TCA cycle rate of 4-5 mmol min-1 kg-1, which is of the same magnitude as the activity of oxyglutarate dehydrogenase and pyruvate dehydrogenase, suggesting that these enzymes may be rate limiting for oxygen uptake when an isolated muscle is exercising[10759582]# Contains thiamine diphosphate. It is a component (in multiple copies) of the multienzyme pyruvate dehydrogenase complex in which it is bound to a core of molecules of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, which also binds multiple copies of EC 1.8.1.4, dihydrolipoyl dehydrogenase. It does not act on free lipoamide or lipoyllysine, but only on the lipoyllysine residue in EC 2.3.1.12. pyruvate dehydrogenase (acetyl-transferring) RL00183 phospholipase a2 eicosanoid synthesis/arachidonic acid release and subsequent eicosanoid formation/prostaglandin synthesis 3.1.1.4 Human 9606 Cellular Processes:Immune System:Fc epsilon RI signaling pathway:map04664#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592#Environmental Information Processing:Signal Transduction:MAPK signaling pathway:map04010#Environmental Information Processing:Signal Transduction:VEGF signaling pathway:map04370#Cellular Processes:Nervous System:Long-term depression:map04730#Cellular Processes:Endocrine System:GnRH signaling pathway:map04912# 10435206, Differences in patients' responses to niacin, a compound causing vasodilation via stimulation of phospholipid dependent signaling cascades, defines more homogeneous patient subgroups in which the rate limiting enzyme of this signaling pathway, phospholipase A2 (PLA2), can be studied[10435206]# Also acts on phosphatidylethanolamine, choline plasmalogen and phosphatides, removing the fatty acid attached to the 2-position. Requires Ca2+. phospholipase A2 RL00185 pantothenate kinase coenzyme A ( CoA ) biosynthetic pathway 2.7.1.33 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Pantothenate and CoA biosynthesis:map00770# 14523052,2981478, Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis[14523052]# pantothenate kinase RL00187 methylenetetrahydrofolate reductase methyl group metabolism 1.5.1.20 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:One carbon pool by folate:map00670#Metabolism:Energy Metabolism:Methane metabolism:map00680# 17372271, Although the pathway is a network of interrelated enzymes, redundancy exists; evaluating the rate-limiting enzyme and its interaction with environment and other genes within the same pathway is critical in assessing breast cancer risk[17372271]# A flavoprotein (FAD). Menadione can also serve as an electron acceptor. methylenetetrahydrofolate reductase [NAD(P)H] RL00188 microsomal bile acid coA synthetase cytosolic amidation 6.2.1.7 Human 9606 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10884298, The K(m) was higher for glycine than taurine both in cytosol and the peroxisomal fraction.These results show that the peroxisomal de novo synthesis of bile acids is rate limiting for peroxisomal amidation, and the microsomal bile acid-CoA synthetase is rate limiting for the cytosolic amidation[10884298]# Requires Mg2+ for activity. This membrane-bound enzyme catalyses the first step in the conjugation of bile acids with amino acids, converting bile acids into their acyl-CoA thioesters. The second step involves EC 2.3.1.65, bile acid-CoA:amino acid N-acyltransferase and converts the acyl-CoA thioester into the corresponding N-acyl amidate by conjugation with glycine or taurine [5]. Chenodeoxycholate, deoxycholate, lithocholate and trihydroxycoprostanoate can also act as substrates [6]. cholate---CoA ligase RL00189 oxygen oxidoreductase leukotriene synthesis/first step in the pathway,but the conversion of LTA4 to LTB4 1.13.11.34 Human 9606 Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 1311589,16415251,1357659, 5-lipoxygenase (5-LO) is the rate-limiting enzyme in the synthetic pathway for cysteinyl leukotrienes (CysLTs), bronchoconstricting agents that are overproduced in asthma[16415251]#These results were explained after a comparison of the rates of synthesis of these 5-lipoxygenase metabolites in the presence and absence of added arachidonic acid which led to the conclusion that leukotriene A hydrolase, the enzyme catalysing the formation of LTB4, was saturated with substrate and rate-limiting for LTB4 synthesis during A23187 stimulation[1311589]#Therefore, the present study determined the abundance of the mRNA for arachidonate 5-lipoxygenase (5-LO; arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34), which is the rate-limiting enzyme in leukotriene synthesis, in a series of human brain tumors[1357659]# arachidonate 5-lipoxygenase RL00192 bilirubin uridine diphosphate glucuronosyltransferase the conjugation of bilirubin with glucuronic acid in its excretion process into the bile 2.4.1.17 Human 9606 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983# 16623861, Bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT) is the rate-limiting enzyme for the conjugation of bilirubin with glucuronic acid in its excretion process into the bile[16623861]# This entry denotes a family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines and fatty acids. Some of the activities catalysed were previously listed separately as EC 2.4.1.42, EC 2.4.1.59, EC 2.4.1.61, EC 2.4.1.76, EC 2.4.1.77, EC 2.4.1.84, EC 2.4.1.107 and EC 2.4.1.108. A temporary nomenclature for the various forms, whose delineation is in a state of flux, is suggested in Ref. 1. glucuronosyltransferase RL00195 galactosyltransferase uridine nucleotide cycle that supports lactose synthesis 2.4.1.22 Human 9606 Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 16937399,10092606, Decreased sialylation correlated with an increase in N-linked carbohydrates missing terminal galactose moieties, suggesting that beta-1,4- galactosyltransferase may be rate limiting in our system[16937399]#Together, these results strongly suggest that galactosylation of I-branch is a rate-limiting step in I-branched poly-N-acetyllactosamine synthesis, allowing poly-N-acetyllactosamine extension mostly along the linear poly-N-acetyllactosamine side chain[10092606]# The enzyme is a complex of two proteins, A and B. In the absence of the B protein (alpha-lactalbumin), the enzyme catalyses the transfer of galactose from UDP-galactose to N-acetylglucosamine (EC 2.4.1.90 N-acetyllactosamine synthase). lactose synthase RL00200 protein disulfide isomerase protein folding 5.3.4.1 Human 9606 Human Diseases:Infectious Diseases:Vibrio cholerae infection:map05110#Cellular Processes:Immune System:Antigen processing and presentation:map04612# 16677074, An examination of the pH-dependence and nature of the rate limiting step for the peptide thiol-disulfide oxidase activity of these enzymes reveals that, with the exception of PDIr, they are all remarkably similar[16677074]# Needs reducing agents or partly reduced enzyme; the reaction depends on sulfhydryl-disulfide interchange. protein disulfide-isomerase RL00205 coproporphyrinogen oxidase heme synthesis 1.3.3.3 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 16567402,10787385, During neuronal differentiation, there were increases in the cellular heme levels and increases in the mRNA levels for the rate-limiting enzymes of heme biosynthesis, such as aminolevulinic acid synthase (ALAS; EC 2.3.1.37) and coproporphyrinogen oxidase (EC 1.3.3.3)[16567402]#Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase[10787385]# coproporphyrinogen oxidase RL00209 branched chain oxoacid dehydrogenase BCAA oxidation/branched-chain amino acid catabolism 1.2.4.4 Human 9606 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280# 10562606, We have previously shown that BCAA ingestion increased the activity of branched-chain oxoacid dehydrogenase, the rate-limiting enzyme for BCAA oxidation in muscle, compared with low glycogen alone[10562606]# Contains thiamine diphosphate. It acts not only on 3-methyl-2-oxobutanaoate, but also on 4-methyl-2-oxopentanoate and (S)-3-methyl-2-oxopentanoate, so that it acts on the 2-oxo acids that derive from the action of transaminases on valine, leucine and isoleucine. It is a component of the multienzyme 3-methyl-2-oxobutanoate dehydrogenase complex in which multiple copies of it are bound to a core of molecules of EC 2.3.1.168, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase, which also binds multiple copies of EC 1.8.1.4, dihydrolipoyl dehydrogenase. It does not act on free lipoamide or lipoyllysine, but only on the lipoyllysine residue in EC 2.3.1.168. 3-methyl-2-oxobutanoate dehydrogenase RL00211 argininosuccinic acid synthetase urea production/urea cycle 6.3.4.5 Human 9606 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 11556547,10709858, The enzyme argininosuccinate synthetase (ASS) is the rate limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine, the physiological substrate of all isoforms of nitric oxide synthases (NOS)[11556547]#Evidence suggests that argininosuccinate synthase activity is rate-limiting to high-output NO synthesis and, hence, represents a novel target for the treatment of pathophysiological conditions arising from NO overproduction[10709858]# argininosuccinate synthase RL00213 adenosine kinase adenosine uptake and metabolism 2.7.1.20 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 2154328,8184939,12228764, Relative to normal brain the tumors had significantly lower ATP and GTP levels, essentially normal pool sizes of purine nucleosides and bases, unchanged activities of the salvage enzymes hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and adenosine kinase (659, 456, and 98 nmol/h/mg protein, respectively) and 4-fold higher activities of IMP dehydrogenase (11.6 nmol/h/mg protein); the latter is the rate limiting enzyme for guanylate de novo synthesis[2154328]#The time course of F-AR uptake suggested that the rate-limiting step was not membrane transport but the intracellular phosphorylation by adenosine kinase[8184939]#Adenosine is a potent modulator of immune function, and adenosine kinase (AK), a rate-limiting enzyme for adenosine uptake and metabolism, is a potential mediator of adenosine regulation[12228764]# 2-Aminoadenosine can also act as acceptor. adenosine kinase RL00214 aconitase 4.2.1.3 Human 9606 Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glyoxylate and dicarboxylate metabolism:map00630#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 8115279, The high citrate to isocitrate ratio of about 33:1, compared to the expected value of about 10:1, supports suggestions that citrate to isocitrate oxidation by aconitase is a rate limiting step in prostatic citrate metabolism[8115279]# Besides interconverting citrate and cis-aconitate, it also interconverts cis-aconitate with isocitrate and, hence, interconverts citrate and isocitrate. The equilibrium mixture is 91% citrate, 6% isocitrate and 3% aconitate. cis-Aconitate is used to designate the isomer (Z)-prop-1-ene-1,2,3-tricarboxylate. An iron-sulfur protein, containing a [4Fe-4S] cluster to which the substrate binds. aconitate hydratase RL00215 NMN adenylyltransferase biosynthesis of NAD 2.7.7.1 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Nicotinate and nicotinamide metabolism:map00760# 11966442, BR 5'-monophosphate is then converted to the active metabolite benzamide adenine dinucleotide (BAD) by NMN adenylyltransferase, the rate-limiting enzyme in the biosynthesis of NAD[11966442]# Nicotinate nucleotide can also act as acceptor. See also EC 2.7.7.18 nicotinate-nucleotide adenylyltransferase. nicotinamide-nucleotide adenylyltransferase RL00217 LTC4 synthase formation of cysteinyl leukotrienes 4.4.1.20 Human 9606 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 10222453, The rate limiting step in the formation of cysteinyl leukotrienes is the conversion of LTA4 to LTC4 catalyzed by the enzyme LTC4 synthase[10222453]# The reaction proceeds in the direction of addition. Not identical with EC 2.5.1.18, glutathione transferase. leukotriene-C4 synthase RL00221 CYP39A1 bile acid synthesis 1.14.13.99 Human 9606 12398993, In liver, 7 alpha-hydroxylation of cholesterols, mediated by CYP7A and CYP39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination[12398993]# A heme-thiolate protein (P-450) that is found in liver microsomes and in ciliary non-pigmented epithelium [2]. The enzyme is specific for (24R)-cholest-5-ene-3beta,24-diol as substrate. 24-hydroxycholesterol 7alpha-hydroxylase RL00222 acyl CoA oxidase very-long-chain fatty acid peroxisomal oxidation 1.3.3.6 Human 9606 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592# 12758125, In the present study, the cloning, expression and characterization of the rate-limiting enzyme of the peroxisomal beta-oxidation spiral, acyl CoA oxidase (AOX), from koala (Phascolarctos cinereus) liver is described[12758125]# A flavoprotein (FAD). Acts on CoA derivatives of fatty acids with chain lengths from 8 to 18. acyl-CoA oxidase RL00223 tyrosine hydroxylase the catecholamine biosynthetic pathway 1.14.16.2 Human 9606 Human Diseases:Neurodegenerative Diseases:Parkinson's disease:map05020#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 18208403, The TH (tyrosine hydroxylase) gene encodes the rate-limiting enzyme of catecholamine biosynthesis, and is involved in the pathogenesis of hypertension, but the relationship of its variants with hypertension has not been extensively studied[18208403]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by EC 2.7.11.27, [acetyl-CoA carboxylase] kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tyrosine 3-monooxygenase RL00224 Heme oxygenase CO generation,degrades heme/ production of bilirubin/ heme degradation pathway 1.14.99.3 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 10353745,10644516,10349844, Heme oxygenase-1 (HO-1), which is the rate-limiting enzyme in heme catabolism, was also associated with activated macrophages[10353745]#Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme catabolism and presumably is involved in cellular iron homeostasis[10644516]#Heme oxygenase is a rate-limiting enzyme in heme catabolism that cleaves heme to form biliverdin, carbon monoxide, and iron[10349844]# Requires NAD(P)H and EC 1.6.2.4, NADPH---hemoprotein reductase. The terminal oxygen atoms that are incorporated into the carbonyl groups of pyrrole rings A and B of biliverdin are derived from two separate oxygen molecules [4]. The third oxygen molecule provides the oxygen atom that converts the alpha-carbon to CO. The central iron is kept in the reduced state by NAD(P)H. heme oxygenase RL00225 GTP cyclohydrolase 1 BH4 synthesis/the biosynthesis of tetrahydrobiopterin (BH(4)),a natural cofactor for tyrosine and tryptophan hydroxylases 3.5.4.16 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 18598896, BACKGROUND: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling[18598896]# The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit; the recyclization may be non-enzymic. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 4.2.3.12 (6-pyruvoyltetrahydropterin synthase) [3]. GTP cyclohydrolase I RL00226 phenylalanine hydroxylase hepatic phenylalanine metabolism 1.14.16.1 Human 9606 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400# 16402341, Cumulatively these findings suggested that TD was related to phenylalanine metabolism and thus that sequence variants in the gene for phenylalanine hydroxylase (PAH), the rate-limiting enzyme in the catabolism of phenylalanine, could be associated with TD susceptibility[16402341]# The active centre contains mononuclear iron(II). The reaction involves an arene oxide that rearranges to give the phenolic hydroxy group. This results in the hydrogen at C-4 migrating to C-3 and in part being retained. This process is known as the NIH-shift. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34, 6,7-dihydropteridine reductase, or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. phenylalanine 4-monooxygenase RL00227 Aromatase estrogen biosynthesis 1.14.14.1 Human 9606 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Xenobiotics Biodegradation and Metabolism:gamma-Hexachlorocyclohexane degradation:map00361#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 14501171,1339246,10690899,12957661, Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer[14501171]#Aromatase, the cytochrome P450 Cyp19 enzyme, catalyzes the rate-limiting step in estrogen biosynthesis[10690899]#We studied in vitro the effects of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) on: 1) mature human granulosa cell proliferation and steroidogenesis; 2) intra-cellular second messenger (cAMP) generation, and the effects of cAMP analogues on cell function; and 3) mRNA expression of the rate limiting enzymes for progesterone and oestradiol synthesis namely: Cholesterol side chain cleavage (P450 SCC), Aromatase (P450 Arom); and 4) LH receptor mRNA expression[1339246]#Aromatase is the rate limiting enzyme that catalyzes the conversion of androgens to estrogens[12957661]# A group of heme-thiolate proteins (P-450), acting on a wide range of substrates including many xenobiotics, steroids, fatty acids, vitamins and prostaglandins; reactions catalysed include hydroxylation, epoxidation, N-oxidation, sulfooxidation, N-, S- and O-dealkylations, desulfation, deamination, and reduction of azo, nitro and N-oxide groups. Together with EC 1.6.2.4, NADPH---hemoprotein reductase, it forms a system in which two reducing equivalents are supplied by NADPH. Some of the reactions attributed to EC 1.14.15.3, alkane 1-monooxygenase, belong here. unspecific monooxygenase RL00228 cyclooxygenase the production of prostanoids/prostaglandin synthesis 1.14.99.1 Human 9606 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 10226539,10395693,10024686, The best known function of NSAIDs action is to block the enzyme cyclooxygenase, the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins[10226539]#The enzyme cyclooxygenase (COX) is a rate-limiting step in PG production[10395693]#One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX)[10024686]# This enzyme acts both as a dioxygenase and as a peroxidase. prostaglandin-endoperoxide synthase RL00229 cholesterol 7alpha-hydroxylase bile acid synthesis/the synthesis of the cofactor for PAH(phenylalanine hydroxylase ) 1.14.13.17 Human 9606 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10588945,8258956, Studies involved measurements of specific activities of four enzymes participating in the maintenance of hepatic cholesterol metabolism: HMG-CoA-reductase, the rate limiting enzyme of cholesterol synthesis; cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis; acyl CoA: cholesterol acyltransferase, the enzyme responsible for esterification of cholesterol; and cholesterol ester hydrolase (CEH), an enzyme which hydrolyzes cholesterol[8258956]#The cloned human oxysterol 7alpha-hydroxylase (CYP7B1) cDNA encodes a polypeptide of 506 amino acid residues that shares 40% sequence identity to human cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver[10588945]# A heme-thiolate protein (P-450). cholesterol 7alpha-monooxygenase RL00230 3-hydroxy-methylglutaryl coenzyme A cholesterol synthesis/the isoprenoid biosynthetic pathway 1.1.1.34 Human 9606 Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 18815589, HMGCR catalyzes the rate-limiting step in cholesterol biosynthesis, and also plays a significant role in cholesterol homeostasis[18815589]# The enzyme is inactivated by EC 2.7.11.31 {[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase} and reactivated by EC 3.1.3.47 {[hydroxymethylglutaryl-CoA reductase (NADPH)]-phosphatase}. hydroxymethylglutaryl-CoA reductase (NADPH) RL00231 Tryptophan hydroxylase the biosynthesis of serotonin (5-HT)/ melatonin biosynthesis 1.14.16.4 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 10327914,10483053, OBJECTIVE: Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin[10327914]#Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been reported from the coding sequence of this gene[10483053]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by a Ca2+-activated protein kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tryptophan 5-monooxygenase RL00232 aromatic amino acid decarboxylase renal dopamine formation 4.1.1.28 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340#Metabolism:Amino Acid Metabolism:Phenylalanine metabolism:map00360#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Metabolism:Biosynthesis of Secondary Metabolites:Indole and ipecac alkaloid biosynthesis:map00901#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 15900211,17017570, These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g[15900211]#In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxyphenylserine (DOPS), was converted to norepinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxylase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase[17017570]# A pyridoxal-phosphate protein. The enzyme also acts on some other aromatic L-amino acids, including L-tryptophan. aromatic-L-amino-acid decarboxylase RL00233 dihydropyrimidine dehydrogenase 5-fluorouracil (5-FU) chemotherapy catabolic pathway 1.3.1.2 Human 9606 Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 10887632,10473079,10853015, In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism[10473079]#An alternate approach involves the inhibition of gastrointestinal degradation via coadministration of an inhibitor of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism[10887632]#Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule[10853015]# Also acts on dihydrothymine. dihydropyrimidine dehydrogenase (NADP+) RL00234 gamma-glutamylcysteine synthetase(gamma-GCShs) glutathione synthesis 6.3.2.2 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 11353135,10218647, Glutamate cysteine ligase (GCL; also referred to as gamma-glutamylcysteine synthetase, GCS) catalyzes the rate-limiting step of glutathione synthesis[11353135]#OxLDL increased the intracellular levels of reactive oxygen species (ROS) and stimulated the expression of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for the GSH synthesis, the mitogen-activated protein kinase (MAPK) activity, and the AP-1-DNA binding activity[10218647]# Can use L-aminohexanoate in place of glutamate. glutamate---cysteine ligase RL00235 hormone-sensitive lipase cholesteryl ester and diacylglycerol hydrolysis/lipolysis/intracellular TG hydrolysis 3.1.1.79 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910# 11246809, Translocation of hormone-sensitive lipase, the rate-limiting enzyme of lipolysis, to the lipid droplet seems to be an important step during lipolytic activation[11246809]# This enzyme is a serine hydrolase. Compared with other lipases, hormone-sensitive lipase has a uniquely broad substrate specificity. It hydrolyses all acylglycerols (triacylglycerol, diacylglycerol and monoacylglycerol) [2,3,4] as well as cholesteryl esters [2,4], steroid fatty acid esters [5], retinyl esters [6] and p-nitrophenyl esters [4,7]. It exhibits a preference for the 1- or 3-ester bond of its acylglycerol substrate compared with the 2-ester bond [8]. The enzyme shows little preference for the fatty acids in the triacylglycerol, although there is some increase in activity with decreasing chain length. The enzyme activity is increased in response to hormones that elevate intracellular levels of cAMP. hormone-sensitive lipase RL00236 carnitine palmitoyltransferase 1a fatty acid metabolism/fatty acid oxidation 2.3.1.21 Human 9606 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 11371554,11356163, Carnitine palmitoyltransferase I is assumed to be rate limiting for beta-oxidation in all tissues[11356163]#Hypoxia prevented the known LCFA-induced accumulation of mRNA encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme that catalyzes the rate-limiting step in mitochondrial fatty acid oxidation (FAO)[11371554]# Broad specificity to acyl group, over the range C8 to C18; optimal activity with palmitoyl-CoA. cf. EC 2.3.1.7 carnitine O-acetyltransferase and EC 2.3.1.137 carnitine O-octanoyltransferase. carnitine O-palmitoyltransferase RL00237 5-aminolevulinate synthase hepatic heme biosynthesis 2.3.1.37 Human 9606 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 11202050,11368326, mutations in the UPGD gene and in the HFE gene affected in haemochromatosis, as well as genetically steered inducibilities of the genes programming for CYP4501A and the rate-limiting enzyme in haem synthesis, 5-aminolevulinate synthase[11202050]#While ALAS induction is necessary for increased heme synthesis, these data indicate that other enzymes, in particular coproporphyrinogen oxidase, represent down-stream rate-limiting steps[11368326]# A pyridoxal-phosphate protein. The enzyme in erythrocytes is genetically distinct from that in other tissues. 5-aminolevulinate synthase RL00238 phosphofructokinase glycolysis 2.7.1.11 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 10444344,10323269,10742704, Time-response studies with Ca(2+)-ionophore A23187 have revealed dual effects on the distribution of phosphofructokinase (PFK) (EC 2.7.1.11), the rate-limiting enzyme of glycolysis, between the cytoskeletal and cytosolic (soluble) fractions of the cell[10444344]#We show that taxol affects both levels of regulation of glycolysis in melanoma cells; it decreases the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two allosteric stimulatory signal molecules of glycolysis, and also causes a detachment of phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11), the rate-limiting enzyme of glycolysis, from the cytoskeleton of B16 melanoma cells[10323269]#We studied muscle histology and measured the activities of the rate-limiting enzymes of anaerobic glycolysis (phosphofructokinase, PFK), glycogenolysis (phosphorylase), citric acid cycle (alpha-ketoglurate dehydrogenase, KGDH) and fatty acid oxidation (carnitinepalmitoyl transferase I and II, CPT I and II) from biopsies of the vastus lateralis muscle at baseline and after 3 and 6 months[10742704]# D-Tagatose 6-phosphate and sedoheptulose 7-phosphate can act as acceptors. UTP, CTP and ITP can act as donors. Not identical with EC 2.7.1.105 6-phosphofructo-2-kinase. 6-phosphofructokinase RL00240 ATP-dependent citrate lyase the de novo synthesis of lipids and cholesterol 6.2.1.5 Human 9606 Metabolism:Carbohydrate Metabolism:C5-Branched dibasic acid metabolism:map00660#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 16101500,6109001, The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase)[16101500]#These data indicate preferential localization of ATP-citrate lyase in cholinergic nerve endings, and indicate that this enzyme is not a rate limiting step in the synthesis of the acetyl moiety of ACh in brain.[6109001]# succinate---CoA ligase (ADP-forming) RL00242 acetyl CoA carboxylase the de novo synthesis of lipids and cholesterol 6.4.1.2 Human 9606 Metabolism:Biosynthesis of Secondary Metabolites:Tetracycline biosynthesis:map00253#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 15607568, At high (supraphysiological) concentrations of GLA, the specific downregulation of FAS gene expression leads to accumulation of the substrate for FAS, malonyl-CoA, that, as a result of FAS blockade, continue to be generated by the rate-limiting enzyme of the fatty acid biosynthetic pathway acetyl-CoA carboxilase, which is not inhibited in the absence of FAS-catalyzed long chain endogenous fatty acids[15607568]# A biotinyl-protein. Also catalyses transcarboxylation; the plant enzyme also carboxylates propanonyl-CoA and butanoyl-CoA. acetyl-CoA carboxylase RL00243 glycogen synthase nonoxidative pathway/glycogen synthesis of skeletal muscle 2.4.1.11 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 10684630,10222257, As the GPI-PLC reaction is rate limiting, the efficiency of the two-step anchor cleavage was significantly increased when insulin was present together with glucose as compared to glucose alone[10684630]#Protein targeting to glycogen/PPP1R5 has recently been identified as a potential regulator of glycogen synthase, the rate-limiting enzyme of the insulin-induced glycogenesis[10222257]# The accepted name varies according to the source of the enzyme and the nature of its synthetic product (cf. EC 2.4.1.1, phosphorylase). Glycogen synthase from animal tissues is a complex of a catalytic subunit and the protein glycogenin. The enzyme requires glucosylated glycogenin as a primer; this is the reaction product of EC 2.4.1.186 (glycogenin glucosyltransferase). A similar enzyme utilizes ADP-glucose (EC 2.4.1.21, starch synthase). glycogen(starch) synthase RL00244 N-acetyltransferase melatonin synthesis 2.3.1.5 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232#Metabolism:Xenobiotics Biodegradation and Metabolism:Trinitrotoluene degradation:map00633# 10471401, In our previous studies, the opioid receptors located on pinealocytes have been identified and characterized, and these receptors have been found to play a stimulatory role in melatonin synthesis by activating the rate limiting enzyme, N-acetyltransferase (NAT)[10471401]# Wide specificity for aromatic amines, including serotonin; also catalyses acetyl-transfer between arylamines without CoA. arylamine N-acetyltransferase RL00245 arylalkylamine N-acetyltransferase melatonin synthesis 2.3.1.87 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 18569588, The melatonin rhythm is arguably the best marker for the phase of the endogenous "biological clock." Arylalkylamine N-acetyltransferase (AANAT) is known to catalyze the acetylation of serotonin, a rate-limiting process in melatonin synthesis[18569588]# Narrow specificity towards 2-arylethylamines, including serotonin (5-hydroxytryptamine), tryptamine, 5-methoxytryptamine and phenylethylamine. This is the penultimate enzyme in the production of melatonin (5-methoxy-N-acetyltryptamine) and controls its synthesis (cf. EC 2.1.1.4, acetylserotonin O-methyltransferase). Differs from EC 2.3.1.5 arylamine N-acetyltransferase. aralkylamine N-acetyltransferase RL00247 ornithine decarboxylase polyamine metabolism 4.1.1.17 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 9368191,6190690, Another suggestion is that these kinases may also participate in the post-translational regulation of ornithine decarboxylase, the rate-limiting step in the polyamine biosynthetic pathway[6190690]#Treatment with alpha-difluoromethylornithine (DFMO), a selective inhibitor of the rate-limiting biosynthetic enzyme ornithine decarboxylase, produced dose-dependent inhibition of the respiratory burst in PMNs that were primed by these agents and subsequently activated by formyl-Met-Leu-Phe (fMLP)[9368191]# A pyridoxal-phosphate protein. ornithine decarboxylase RL00248 Thymidylate synthase the synthesis of pyrimidine nucleotides 2.1.1.45 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:One carbon pool by folate:map00670#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 12457437,16077970,15598787,14689231,16617381, Thymidylate synthase (TS) catalyses the de novo synthesis of deoxythymidylate and is a key rate-limiting enzyme of DNA synthesis[12457437]#Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis[15598787]#Thymidylate synthase (TS) is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides, required for DNA synthesis, and is also a critical target for fluoropyrimidines, which are widely used in the treatment of gastrointestinal tumours[16077970]#Thymidylate synthase (TS), the target enzyme of FUra, and dihydropyrimidine dehydrogenase (DPD), the rate-limiting catabolic enzyme of pyrimidines, have both been reported to be predictors of the response to FUra-based chemotherapies[14689231]#AIM: Thymidylate synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway, and represents a cellular target of antimetabolite drug 5-fluorouracil[16617381]# thymidylate synthase RL00249 nitric oxide synthase NO synthesis 1.14.13.39 Human 9606 Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Cellular Processes:Nervous System:Long-term depression:map04730#Human Diseases:Cancers:Small cell lung cancer:map05222# 16269316, Three separate genes encode for nitric-oxide synthase (NOS), the rate-limiting enzyme in NO production, all of which are expressed within brain tissue[16269316]# The enzyme in brain, but not that induced in lung or liver by endotoxin, requires Ca2+. The stoichiometry is not clear, but may involve a two-electron and a one-electron oxidation step. nitric-oxide synthase RL00250 aldose reductase/NADPH-dependent aldo-keto reductase polyol pathway/ethanologenesis of D-xylose 1.1.1.21 Human 9606 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 11095596,15736047, PURPOSE: Aldose reductase (ALR2) is the first and rate-limiting enzyme of the polyol pathway and is involved in the pathogenesis of diabetic retinopathy[11095596]#Aldose reductase is an NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway that is implicated in the complications of diabetes[15736047]# Has wide specificity. aldehyde reductase RL00251 n acetylglucosamine epimerase sialic acid biosynthesis 5.1.3.14 Human 9606 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530# 10334995,11326336,8439453, Uridine diphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) is an enzyme that catalyzes an early, rate-limiting step in the sialic acid biosynthetic pathway[10334995]#The basic defect consists of the very rare occurrence of failed feedback inhibition of a rate-limiting enzyme, in this case uridinediphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase, by a downstream product, in this case cytidine monophosphate (CMP)-NeuAc[11326336]#Sialuria is a rare inborn error of sialic acid (NeuAc) metabolism resulting from failure of CMP-NeuAc to adequately feedback inhibit the rate-limiting enzyme in sialic acid synthesis, UDP N-acetylglucosamine (UDP-GlcNAc) 2-epimerase[8439453]# The enzyme hydrolyses the product to UDP and N-acetyl-D-mannosamine. UDP-N-acetylglucosamine 2-epimerase RL00253 phosphatidate phosphohydrolase triacylglycerol(TG) synthesis/the de novo synthesis of lipids and cholesterol 3.1.3.4 Human 9606 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600#Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 6088251, According to current concepts, soluble phosphatidic-acid phosphatase, converting phosphatidic acid into a diglyceride, is a rate-limiting enzyme in the hepatic biosynthesis of triglycerides[6088251]# phosphatidate phosphatase RL00256 branched-chain alpha-keto acid dehydrogenase complex the branched-chain amino acid catabolism 1.8.1.4 Human 9606 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 11641455, The rate-limiting step of branched-chain amino acid oxidation is performed by the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKAD), which is regulated by a deactivating kinase[11641455]# A flavoprotein (FAD). A component of the multienzyme 2-oxo-acid dehydrogenase complexes. In the pyruvate dehydrogenase complex, it binds to the core of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, and catalyses oxidation of its dihydrolipoyl groups. It plays a similar role in the oxoglutarate and 3-methyl-2-oxobutanoate dehydrogenase complexes. Another substrate is the dihydrolipoyl group in the H-protein of the glycine-cleavage system (click here for diagram), in which it acts, together with EC 1.4.4.2, glycine dehydrogenase (decarboxylating), and EC 2.1.2.10, aminomethyltransferase, to break down glycine. It can also use free dihydrolipoate, dihydrolipoamide or dihydrolipoyllysine as substrate. This enzyme was first shown to catalyse the oxidation of NADH by methylene blue; this activity was called diaphorase. The glycine cleavage system is composed of four components that only loosely associate: the P protein (EC 1.4.4.2), the T protein (EC 2.1.2.10), the L protein (EC 1.8.1.4) and the lipoyl-bearing H protein [6]. dihydrolipoyl dehydrogenase RL00257 Inosine monophosphate dehydrogenase the de novo synthesis of guanine nucleotides from IMP 1.1.1.205 Human 9606 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983# 17100698,10194364,10417742,15940263,10390601,16243838,9766533,16647299, Mycophenolic acid (MPA) is a highly selective, non-competitive and reversible inhibitor of the inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides[17100698]#Inosine-5'-monophosphate dehydrogenase (IMPDH) catalyzes the K+-dependent reaction IMP + NAD + H2O --> XMP + NADH + H+ which is the rate-limiting step in guanine nucleotide biosynthesis[10194364]#Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP[15940263]#These properties reflect the fact that IMPDH is a rate-limiting enzyme in the new synthesis of the purine guanosine triphosphate (GTP), which modulates both exocytotic insulin secretion and DNA synthesis, as well as a number of other critical cellular functions within the beta-cell[10417742]#Inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, is a major therapeutic target[16243838]#Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP[10390601]#Recently, we demonstrated that downregulation of inosine-5'-monophosphate dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 1.2.1.14), the rate-limiting enzyme for guanine nucleotide biosynthesis, is required for p53-dependent growth suppression[9766533]#We evaluated a selection scheme based on the expression of a variant of inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in the de novo purine biosynthesis pathway[16647299]# The enzyme acts on the hydroxy group of the hydrated derivative of the substrate. IMP dehydrogenase RL00261 spermidine/spermine N-acetyltransferase the polyamine catabolic pathway 2.3.1.57 Human 9606 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 16207710,16262603,12827295, The original hypothesis was that analogue induction of the rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) provided substrate for the peroxisomal acetylpolyamine oxidase (PAO), resulting in a decrease in polyamine pools through catabolism, oxidation, and excretion of acetylated polyamines and the production of toxic aldehydes and H2O2[16207710]#It has been shown that the NSAID sulindac induces apoptosis and suppresses carcinogenesis, in part, by a mechanism leading to the transcriptional activation of the gene encoding SSAT (spermidine/spermine N1-acetyltransferase), a rate-limiting enzyme in polyamine catabolism[16262603]#Initially, human polyamine catabolism was assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO)[12827295]# Acts on propane-1,3-diamine, pentane-1,5-diamine, putrescine, spermidine (forming N1- and N8-acetylspermidine), spermine, N1-acetylspermidine and N8-acetylspermidine. diamine N-acetyltransferase RL00262 Stearoyl-CoA desaturase monounsaturated fatty acid synthesis,oleic acid synthesis, 1.14.19.1 Human 9606 Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040# 10484602,11396956, A key enzyme involved in this process is the membrane-bound stearoyl-CoA desaturase (SCD) which is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids[10484602]#Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the cellular synthesis of monounsaturated fatty acids mainly oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, cholesterol esters, waxes, and triglycerides[11396956]# An iron protein. The rat liver enzyme is an enzyme system involving cytochrome b5 and EC 1.6.2.2, cytochrome-b5 reductase. The ferricytochrome b5 produced is reduced by NADH and cytochrome-b5 reductase (EC 1.6.2.2). stearoyl-CoA 9-desaturase RL00264 glutamate decarboxylase gama-amino butrylic acid (GABA) production 4.1.1.15 Human 9606 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Human Diseases:Metabolic Disorders:Type I diabetes mellitus:map04940#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 17044036, We observed that a 48-hr treatment with the estrogen receptor antagonists ICI 182780 and tamoxifen decreased the level of glutamate decarboxylase (GAD)-65, a rate-limiting gamma-aminobutyric acid (GABA)-synthesizing enzyme, in a dissociated hippocampal neuronal culture[17044036]# A pyridoxal-phosphate protein. The brain enzyme also acts on L-cysteate, 3-sulfino-L-alanine and L-aspartate. glutamate decarboxylase RL00265 S-Adenosylmethionine decarboxylase polyamine biosynthesis pathway 4.1.1.50 Human 9606 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271# 2775206,7945201,11923270, The rate-limiting enzymes in polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), are negatively regulated by the polyamines spermidine and spermine[2775206]#S-Adenosylmethionine decarboxylase (AdoMetDC), a rate-limiting enzyme in polyamine biosynthesis, is regulated by polyamines at the levels of both transcription and translation[7945201]#The two rate-limiting synthetic enzymes were also present, and their activities were stimulated dramatically by addition of serum to the culture medium[11923270]# The Escherichia coli enzyme contains a pyruvoyl group. adenosylmethionine decarboxylase RL00266 histidine decarboxylase histamine synthesis 4.1.1.22 Human 9606 Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340# 11566179, We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery[11566179]# A pyridoxal-phosphate protein (in animal tissues). The bacterial enzyme has a pyruvoyl residue as prosthetic group. histidine decarboxylase RL00267 ribonucleotide reductase deoxyribonucleotide synthesis 1.17.4.1 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Cellular Processes:Cell Growth and Death:p53 signaling pathway:map04115#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 16925573,12147300,10441745,11489836,15571292, Ribonucleotide reductase (RR) is the enzyme that catalyses the rate-limiting step in DNA synthesis, the production of deoxynucleotides[16925573]#Ribonucleotide reductase is the rate-limiting enzyme for the de novo synthesis of deoxynucleoside triphosphates and therefore represents a good target for cancer chemotherapy[12147300]#This gene encodes the large subunit (M1) of ribonucleotide reductase, the heterodimeric enzyme that catalyzes the rate-limiting step in deoxyribonucleotide synthesis[10441745]#Recently, gemcitabine resistance has been associated with the up-regulation of mRNA and protein levels of the ribonucleotide reductase M2 subunit (RR-M2), a rate-limiting enzyme in DNA synthesis that is cell cycle regulated[11489836]#Ribonucleotide reductase (EC1.17.4.1; RR) catalyzes the rate-limiting step in DNA synthesis and plays a critical role in maintaining crucial substrates for DNA repair[15571292]# This enzyme is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. An iron protein. While the enzyme is activated by ATP, it is inhibited by dATP [3,6]. ribonucleoside-diphosphate reductase RL00268 oxido:lanosterol cyclase/Oxidosqualene--lanosterol cyclase cholesterol biosynthetic pathway 5.4.99.7 Human 9606 Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 15763540, This hypocholesterolemic effect was likely due to the inhibition of the oxido:lanosterol cyclase (OSC), a rate-limiting enzyme in the cholesterol biosynthetic pathway[15763540]# lanosterol synthase RL00270 Tyrosinase melanin synthesis 1.14.18.1 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Riboflavin metabolism:map00740#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Cellular Processes:Endocrine System:Melanogenesis:map04916#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 10870514,10671066, To distinguish these two possibilities, the present study examined the effects of latanoprost on tyrosinase activity (the rate-limiting step for melanin synthesis) and mitotic index of cultured melanoma lines[10870514]#Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone[10671066]# A group of copper proteins that also catalyse the reaction of EC 1.10.3.1 catechol oxidase, if only 1,2-benzenediols are available as substrate. monophenol monooxygenase RL00271 glucose-6-phosphate dehydrogenase pentose phosphate pathway (PPP)/the GSH- and NADPH-dependent H(2)O(2) elimination by PC12 cells/NADPH production 1.1.1.49 Human 9606 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030# 18029214,10329961, Furthermore, the activity and transcript level of the lipogenic enzyme glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway, were also about 2-fold higher than that of the wild-type; these data corroborate the flux analysis results[18029214]#The principal intracellular reductant NADPH is mainly produced by the pentose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme, and by 6-phosphogluconate dehydrogenase[10329961]# Also acts slowly on beta-D-glucose and other sugars. Certain preparations reduce NAD+ as well as NADP+. glucose-6-phosphate dehydrogenase RL00272 Uridine-cytidine nucleoside kinase pyrimidine-nucleotide salvage pathway 2.7.1.48 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 195585,9923963,15735337, Further, comparisons of the Km values of isolated uridine kinases with those for cellular uptake of pyrimidine nucleosides and their rate of intracellular phosphorylation suggest that nucleoside-transport systems play a rate-limiting role in nucleoside analogue activation and consequently that it is impossible to estimate the Km of uridine kinase in the intact cell[195585]#The activity of uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48), the rate-limiting enzyme of the UMP salvage pathway, was measured in human ovaries and ovarian carcinomas, in a spectrum of six rat hepatomas of different growth rates and in eleven normal rat tissues of high and low cell renewal rates[9923963]#Uridine-cytidine nucleoside kinase 2 (UCK2) is the rate-limiting enzyme in the pyrimidine-nucleotide salvage pathway[15735337]# Cytidine can act as acceptor; GTP and ITP can act as donors. uridine kinase RL00275 glutamine-fructose-6-phosphate amidotransferase hexosamine synthesis 2.6.1.16 Human 9606 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 15308130,9028721, We hypothesized that variants of GFPT1 encoding glutamine-fructose-6-phosphate amidotransferase, the rate limiting enzyme in this pathway, could increase GFPT1 gene expression and thus susceptibility to diabetes and diabetic nephropathy[15308130]#Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc beta-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residues on intracellular proteins[9028721]# Although the overall reaction is that of a transferase, the mechanism involves the formation of ketimine between fructose 6-phosphate and a 6-amino group from a lysine residue at the active site, which is subsequently displaced by ammonia (transamidination). glutamine---fructose-6-phosphate transaminase (isomerizing) RL00276 phosphoribosyl pyrophosphate amidotransferase the purine de novo pathway 2.4.2.14 Human 9606 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 6327016, The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# amidophosphoribosyltransferase RL00277 Lipoprotein lipase the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism 3.1.1.34 Human 9606 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10650951,10077655, Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of serum triglycerides associated with the lipoprotein particles very low density lipoprotein and chylomicrons[10650951]#The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism[10077655]# Hydrolyses triacylglycerols in chylomicrons and low-density lipoproteins. Also hydrolyses diacylglycerol. lipoprotein lipase RL00278 serine palmitoyltransferase SM biosynthesis 2.3.1.50 Human 9606 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600# 10722759,10818445,10971324, Further investigation using a labeled substrate for serine palmitoyltransferase, the rate-limiting enzyme in the pathway, resulted in an accumulation of label in ceramide upon etoposide treatment[10722759]#In data obtained from intact cell radiolabeling studies, it was observed that the first and rate-limiting enzyme in de novo synthesis, serine palmitoyltransferase, is activated and controls the production of ceramide through this pathway[10818445]#Furthermore, the activity of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, was increased in nicotinamide-treated cells[10971324]# A pyridoxal-phosphate protein. serine C-palmitoyltransferase RL00279 tryptophan 2,3-dioxygenase kynurenine pathway/tryptophan catabolism 1.13.11.11 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 10709788,10966936,12766158, The goal of this study was to determine the localization of Quin in unstimulated mice under conditions where rate-limiting control of the pathway by both TDO and IDO was by-passed[10709788]#Indoleamine 2,3-dioxgyenase (IDO) is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyzes the first and rate-limiting step in the major pathway of tryptophan metabolism, the kynurenine pathway[12766158]#Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels[10966936]# A protohemoprotein. In mammals, the enzyme appears to be located only in the liver. This enzyme, together with EC 1.13.11.52, indoleamine 2,3-dioxygenase, catalyses the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism [5]. The enzyme is specific for tryptophan as substrate, but is far more active with L-tryptophan than with D-tryptophan [2]. tryptophan 2,3-dioxygenase RL00281 delta-aminolevulinic acid synthase heme biosynthesis 4.2.1.24 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 10634305,10787385, The activities of delta-aminolevulinic acid synthase, a rate-limiting enzyme in the heme biosynthesis, and porphobilinogen synthase in the liver of rhIL-1beta-induced fevered rat were significantly lower than those in the control, whereas the activity of heme oxygenase, a key enzyme in the heme-degradative pathway, markedly increased in the fevered rat[10634305]#Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase[10787385]# The fungal enzyme is a metalloprotein. porphobilinogen synthase RL00282 Thymidine phosphorylase etabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd,doxifluridine) 2.4.2.4 Human 9606 Human Diseases:Cancers:Bladder cancer:map05219#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 11585972,10853015,15134221, This is most likely attributable to the upregulation of thymidine phosphorylase (the rate-limiting enzyme needed to convert capecitabine to 5-fluorouracil [5-FU]) in tumor cells following radiotherapy[11585972]#Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule[10853015]#The most important are the major target enzyme, thymidylate synthase (TS) and the rate limiting enzyme in the degradation pathway, dihydropyrimidine dehydrogenase (DPD), equally important for the analogue capecitabine is thymidine phosphorylase (TP), which is rate limiting for activation of this prodrug[15134221]# The enzyme in some tissues also catalyses deoxyribosyltransferase reactions of the type catalysed by EC 2.4.2.6, nucleoside deoxyribosyltransferase. thymidine phosphorylase RL00283 hexose diphosphatase reductive pentose phosphate cycle 3.1.3.11 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Energy Metabolism:Carbon fixation:map00710# 8530070, Although FBP is a rate-limiting enzyme in gluconeogenesis, using both parametric and nonparametric analysis there was no evidence for linkage of FBP to diabetes in these families[8530070]# The animal enzyme also acts on sedoheptulose 1,7-bisphosphate. fructose-bisphosphatase RL00284 deoxythymidylate kinase the biosynthesis of deoxythymidine triphosphate 2.7.4.9 Human 9606 Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 164949, Thus, in the infected cell deoxythymidylate kinase is a rate-limiting enzyme in the biosynthesis of deoxythymidine triphosphate[164949]# dTMP kinase RL00285 P450scc steroid synthesis 1.14.15.6 Human 9606 Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 10418987,12137805, The first and rate-limiting step in the synthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by the mitochondrial enzyme, P450scc[10418987]#We conclude from this study that cholesterol is near-saturating for cytochrome P450scc activity in placental mitochondria due to the P450scc displaying a low K(m) for cholesterol resulting from the low and rate-limiting concentration of AR present[12137805]# A heme-thiolate protein. The reaction proceeds in three stages, with hydroxylation at C-20 and C-22 preceding scission of the side-chain at C-20. cholesterol monooxygenase (side-chain-cleaving) RL00294 Aspartate Carbamoyltransferase pyrimidine nucleotide biosynthesis 2.1.3.2 Human 9606 Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 12678497, Recent studies demonstrate that CAD, a rate-limiting enzyme in the de novo synthesis of pyrimidines, is regulated through reversible phosphorylation, Myc-dependent transcriptional changes and caspase-mediated degradation[12678497]# aspartate carbamoyltransferase RL00295 oxoglutarate dehydrogenase complex citric acid cycle 1.2.4.2/2.3.1.61/1.8.1.4 Human 9606 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 15953811,15953809, The enzymes that form the mitochondrial alpha-ketoglutarate- dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes[15953811]#The earliest metabolic consequence of thiamine deficiency is a selective loss in activity of the thiamine diphosphate-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha-KGDH), a rate-limiting tricarboxylic acid cycle enzyme[15953809]# A multimer (24-mer) of this enzyme forms the core of the multienzyme complex, and binds tightly both EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively succinylated by EC 1.2.4.2, and the only observed direction catalysed by EC 2.3.1.61 is that where this succinyl group is passed to coenzyme A. dihydrolipoyllysine-residue succinyltransferase RL00003 phosphoenolpyruvate carboxykinase (GTP) Glyceroneogenesis 4.1.1.32 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 14739071, The rate-limiting enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK-C)[14739071]# ITP can act as phosphate donor. phosphoenolpyruvate carboxykinase (GTP) RL00004 glycogen phosphorylase intracellular glycogen breakdown 2.4.1.1 Human 9606 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 9590562,11368340, Muscle glycogen phosphorylase (MGP), the rate-limiting enzyme for glycogen metabolism in skeletal muscle, is neurally regulated[9590562]#GP is the rate-limiting enzyme in intracellular glycogen breakdown[11368340]# The accepted name should be qualified in each instance by adding the name of the natural substrate, e.g. maltodextrin phosphorylase, starch phosphorylase, glycogen phosphorylase. phosphorylase RL00010 hexokinase glycolysis 2.7.1.1 Human 9606 Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 10946615,9199203,18632830, Of glycolytic enzymes, the activity of hexokinase, known as a rate limiting enzyme in glycolysis, is amazingly high in malignant tumor cells[10946615]#Since hexokinase is the first rate limiting enzyme in the glycolytic pathway, elevated levels of Type II like hexokinase in tumors are of great significance in this context[9199203]#Gene array analysis revealed that both hexokinase 1 as the rate-limiting enzyme for 18F-FDG trapping and pancreas-specific glucose transporter 2 were significantly downregulated whereas thymidine kinase 1, responsible for 18F-FLT trapping, was significantly upregulated in the tumor cell lines, compared with normal pancreatic duct cells and pancreatic tumor tissue[18632830]# D-Glucose, D-mannose, D-fructose, sorbitol and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. hexokinase RL00006 acyl-CoA dehydrogenase mitochondrial beta-oxidation 1.1.1.35 Human 9606 Metabolism:Xenobiotics Biodegradation and Metabolism:Caprolactam degradation:map00930#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Xenobiotics Biodegradation and Metabolism:Benzoate degradation via CoA ligation:map00632#Metabolism:Xenobiotics Biodegradation and Metabolism:Geraniol degradation:map00281#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592#Metabolism:Lipid Metabolism:Fatty acid elongation in mitochondria:map00062#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 1744086, During oxidation of [U-14C]hexadecanoate by normal human fibroblast mitochondria, only the saturated acyl-CoA and acylcarnitine esters can be detected, supporting the concept that the acyl-CoA dehydrogenase step is rate-limiting in mitochondrial beta-oxidation[1744086]# Also oxidizes S-3-hydroxyacyl-N-acylthioethanolamine and S-3-hydroxyacyl-hydrolipoate. Some enzymes act, more slowly, with NADP+. Broad specificity to acyl chain-length (cf. EC 1.1.1.211 [long-chain-3-hydroxyacyl-CoA dehydrogenase]). 3-hydroxyacyl-CoA dehydrogenase RL00009 Kynurenine hydroxylase tryptophan metabolism 1.14.13.9 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 4018389,10939276, Regulation of the rate-limiting step in dopamine (DA) synthesis was estimated in striatal synaptosomes by measuring the rate of hydroxylation of L-4-[3H]phenylalanine, a substrate of tyrosine hydroxylase (TH)[4018389]#KM is innately low in the brain and similar in activity to indoleamine oxidase, the rate-limiting pathway enzyme[10939276]# A flavoprotein (FAD). kynurenine 3-monooxygenase RL00012 pyridoxamine 5'-phosphate oxidase pyridoxal 5 phosphate (PLP, vitamin B(6)) synthesis 1.4.3.5 Human 9606 Metabolism:Metabolism of Cofactors and Vitamins:Vitamin B6 metabolism:map00750# 9601034,17851041, In particular, pyridoxine- 5'-phosphate oxidase (PNPO), the rate-limiting enzyme in pyridoxal 5'-phosphate (PLP) biosynthesis, is absent in liver and neurally-derived tumors[9601034]# We hypothesized that the gene PNPO (pyridoxine 5'-phosphatase oxidase gene) might be a candidate for susceptibility to schizophrenia because PNPO encodes pyridoxamine 5'-phosphate oxidase (EC 1.4.3.5), a rate-limiting enzyme in pyridoxal 5'-phosphate (PLP, vitamin B(6)) synthesis[17851041]# A flavoprotein (FMN). In Escherichia coli, the coenzyme pyridoxal 5'-phosphate is synthesized de novo by a pathway that involves EC 1.2.1.72 (erythrose-4-phosphate dehydrogenase), EC 1.1.1.290 (4-phosphoerythronate dehydrogenase), EC 2.6.1.52 (phosphoserine transaminase), EC 1.1.1.262 (4-hydroxythreonine-4-phosphate dehydrogenase), EC 2.6.99.2 (pyridoxine 5'-phosphate synthase) and EC 1.4.3.5 (with pyridoxine 5'-phosphate as substrate). N4'-Substituted pyridoxamine derivatives are also oxidized in reaction (1) to form pyridoxal 5'-phosphate and the corresponding primary amine. pyridoxal 5'-phosphate synthase RL00013 transketolase the non-oxidative part of the pentose phosphate pathway, from vanadocytes 2.2.1.1 Human 9606 Metabolism:Biosynthesis of Polyketides and Nonribosomal Peptides:Biosynthesis of ansamycins:map01051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Energy Metabolism:Carbon fixation:map00710# 11072071, In the current study, we cloned a cDNA for transketolase, an essential and rate-limiting enzyme in the non-oxidative part of the pentose phosphate pathway, from vanadocytes[11072071]# A thiamine-diphosphate protein. Wide specificity for both reactants, e.g. converts hydroxypyruvate and R-CHO into CO2 and R-CHOH-CO-CH2OH. Transketolase from Alkaligenes faecalis shows high activity with D-erythrose as acceptor. transketolase RL00014 citrate lyase, de novo synthesis of fatty acids and triglycerides 2.3.3.8 Human 9606 Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 17404227,131232, The normal activity of glucose-6-phosphate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), which supply NADPH for the reduction of acetyl-CoA to fatty acids, would suggest that the change in lipogenesis is of moderate degree, thereb) affecting only the most rate-limiting enzyme, ATP citrate-lyase[131232]#This phenotype is caused by a mild but significant reduction in total energy expenditure paralleled by increased expression of ATP citrate lyase, a rate-limiting step in de novo synthesis of fatty acids and triglycerides[17404227]# The enzyme can be dissociated into components, two of which are identical with EC 4.1.3.34 (citryl-CoA lyase) and EC 6.2.1.18 (citrate---CoA ligase). ATP citrate synthase RL00017 Myo-inositol-1-phosphate (MIP) synthase inositol biosynthesis 3.1.3.25 Human 9606 Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 12479670, MIP synthase is the rate-limiting step in inositol biosynthesis and is highly regulated in response to inositol[12479670]# Acts on five of the six isomers of myo-inositol phosphate, all except myo-inositol 2-phosphate, but does not act on myo-inositol bearing more than one phosphate group. It also acts on adenosine 2'-phosphate (but not the 3'- or 5'- phosphates), sn-glycerol 3-phosphate and glycerol 2-phosphate. Two isoforms are known [4]. inositol-phosphate phosphatase RL00018 alpha-mannosidase 3.2.1.24 Human 9606 Metabolism:Glycan Biosynthesis and Metabolism:Glycan structures - Degradation:map01032#Metabolism:Glycan Biosynthesis and Metabolism:N-Glycan degradation:map00511# 2466460, The rate-limiting step seemed to be the processing of the 19.5 kDa precursor by alpha-mannosidase II[2466460]# Also hydrolyses alpha-D-lyxosides and heptopyranosides with the same configuration at C-2, C-3 and C-4 as mannose. alpha-mannosidase RL00019 sulfoalanine decarboxylase taurine biosynthesis 4.1.1.29 Human 9606 Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 11997111,14553911, Cysteine sulfinic acid decarboxylase (CSD) is the rate-limiting enzyme for biosynthesis of taurine which is essential to biological processes such as development of the brain and eye, reproduction, osmoregulation as well as the anti-inflammatory activity of leukocytes[11997111]#Cysteine sulfinic acid decarboxylase, a rate-limiting enzyme for taurine biosynthesis, has been cloned and sequenced in the mouse, rat and human[14553911]# A pyridoxal-phosphate protein. Also acts on L-cysteate. The 1992 edition of the Enzyme List erroneously gave the name sulfoalanine decarboxylase to this enzyme. sulfinoalanine decarboxylase RL00020 cystathionine-gamma-lyase the synthesis of cysteine from methionine 4.4.1.1 Human 9606 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271#Metabolism:Energy Metabolism:Nitrogen metabolism:map00910#Metabolism:Amino Acid Metabolism:Cysteine metabolism:map00272# 17095121, Cystathionine gamma-lyase is the rate-limiting enzyme for the synthesis of cysteine from methionine and availability of cysteine is a critical factor in glutathione synthesis[17095121]# A multifunctional pyridoxal-phosphate protein. Also catalyses elimination reactions of L-homoserine to form H2O, NH3 and 2-oxobutanoate, of L-cystine, producing thiocysteine, pyruvate and NH3, and of L-cysteine producing pyruvate, NH3 and H2S. cystathionine gamma-lyase RL00021 Carbamyl phosphate synthetase I free ammonia into the urea cycle 6.3.4.16 Human 9606 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 18026163,15050969, CPS1 is a rate-limiting enzyme in urea cycle and is located in mitochondria[18026163]#Carbamyl phosphate synthetase I (CPSI) determines the rate-limiting entry of free ammonia into the urea cycle[15050969]# carbamoyl-phosphate synthase (ammonia) RL00026 Cytidine triphosphate synthetase the de novo synthesis of CTP 6.3.4.2 Human 9606 Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 17681942, Cytidine triphosphate synthetase (CTPS) catalyzes the rate-limiting step in the de novo synthesis of CTP, and both the yeast and human enzymes have been reported to be regulated by protein kinase A or protein kinase C phosphorylation[17681942]# Glutamine can replace NH3. CTP synthase RL00296 pyruvate kinase glycolysis 2.7.1.40 Mouse 10090 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Energy Metabolism:Carbon fixation:map00710# 8751724, Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver[8751724]# UTP, GTP, CTP, ITP and dATP can also act as donors. Also phosphorylates hydroxylamine and fluoride in the presence of CO2. pyruvate kinase RL00297 fatty acid synthase fatty acid biosynthetic pathway 2.3.1.85 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 12131249, INTRODUCTION: The purpose of this study was to investigate whether chronic exercise training attenuates fatty acid synthase, the rate-limiting enzyme for hepatic lipogenesis, and the accumulation of body fat by using obese Zucker rats (OZR) as a model[12131249]# The animal enzyme is a multi-functional protein catalysing the reactions of EC 2.3.1.38 [acyl-carrier-protein] S-acetyltransferase, EC 2.3.1.39 [acyl-carrier-protein] S-malonyltransferase, EC 2.3.1.41 3-oxoacyl-[acyl-carrier-protein] synthase, EC 1.1.1.100 3-oxoacyl-[acyl-carrier-protein] reductase, EC 4.2.1.61 3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase, EC 1.3.1.10 enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) and EC 3.1.2.14 oleoyl-[acyl-carrier-protein] hydrolase. fatty-acid synthase RL00299 carbonic anhydrase CO2 hydration 4.2.1.1 Rat 10116 Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 6772280, Acetazolamide-pretreated rats had the same CO2 uptake as controls after 15 min exposure to CO2, rather than lower uptake as would be expected if carbonic anhydrase were rate-limiting[6772280]# A zinc protein. carbonate dehydratase RL00300 nitric oxide synthase nitric oxide(NO) synthesis 1.14.13.39 Rat 10116 Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Cellular Processes:Nervous System:Long-term depression:map04730#Human Diseases:Cancers:Small cell lung cancer:map05222# 19019231, eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzes the rate-limiting step in the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2)[19019231]# The enzyme in brain, but not that induced in lung or liver by endotoxin, requires Ca2+. The stoichiometry is not clear, but may involve a two-electron and a one-electron oxidation step. nitric-oxide synthase RL00301 xanthine oxidase nucleic acid degradation/purine catabolism 1.17.3.2 Rat 10116 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 12780970, Although aspects of the glutathione antioxidant repertoire were similarly diminished with high-intensity xanthine oxidase stress, low-dose (long duration) xanthine oxidase stress augmented the activities of type II cell glutathione peroxidase and gamma-glutamyl transferase (the rate-limiting enzyme in glutathione synthesis)[12780970]# An iron-molybdenum flavoprotein (FAD) containing [2Fe-2S] centres. Also oxidizes hypoxanthine, some other purines and pterins, and aldehydes (i.e. possesses the activity of EC 1.2.3.1, aldehyde oxidase). Under some conditions the product is mainly superoxide rather than peroxide: RH + H2O + 2 O2 = ROH + 2 O2.- + 2 H+. The enzyme from animal tissues can be converted into EC 1.17.1.4, xanthine dehydrogenase. That from liver exists in vivo mainly as the dehydrogenase form, but can be converted into the oxidase form by storage at -20 _degree_C, by treatment with proteolytic enzymes or with organic solvents, or by thiol reagents such as Cu2+, N-ethylmaleimide or 4-mercuribenzoate. The effect of thiol reagents can be reversed by thiols such as 1,4-dithioerythritol. EC 1.17.1.4 can also be converted into this enzyme by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide. The Micrococcus enzyme can use ferredoxin as acceptor. xanthine oxidase RL00302 xanthine oxidase nucleic acid degradation/purine catabolism 1.17.3.2 Mouse 10090 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 12780970, Although aspects of the glutathione antioxidant repertoire were similarly diminished with high-intensity xanthine oxidase stress, low-dose (long duration) xanthine oxidase stress augmented the activities of type II cell glutathione peroxidase and gamma-glutamyl transferase (the rate-limiting enzyme in glutathione synthesis)[12780970]# An iron-molybdenum flavoprotein (FAD) containing [2Fe-2S] centres. Also oxidizes hypoxanthine, some other purines and pterins, and aldehydes (i.e. possesses the activity of EC 1.2.3.1, aldehyde oxidase). Under some conditions the product is mainly superoxide rather than peroxide: RH + H2O + 2 O2 = ROH + 2 O2.- + 2 H+. The enzyme from animal tissues can be converted into EC 1.17.1.4, xanthine dehydrogenase. That from liver exists in vivo mainly as the dehydrogenase form, but can be converted into the oxidase form by storage at -20 _degree_C, by treatment with proteolytic enzymes or with organic solvents, or by thiol reagents such as Cu2+, N-ethylmaleimide or 4-mercuribenzoate. The effect of thiol reagents can be reversed by thiols such as 1,4-dithioerythritol. EC 1.17.1.4 can also be converted into this enzyme by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide. The Micrococcus enzyme can use ferredoxin as acceptor. xanthine oxidase RL00303 retinal dehydrogenase the metabolism of retinal to retinoic acid 1.2.1.36 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830# 2910311, Under conditions in which retinal dehydrogenase activity is rate-limiting for the metabolism of retinal to retinoic acid, its induction after phenobarbital or ethanol administration may contribute to hepatic vitamin A depletion[2910311]# A metalloflavoprotein (FAD). Acts on both the 11-trans- and 13-cis-forms of retinal. retinal dehydrogenase RL00304 retinal dehydrogenase the metabolism of retinal to retinoic acid 1.2.1.36 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830# 2910311, Under conditions in which retinal dehydrogenase activity is rate-limiting for the metabolism of retinal to retinoic acid, its induction after phenobarbital or ethanol administration may contribute to hepatic vitamin A depletion[2910311]# A metalloflavoprotein (FAD). Acts on both the 11-trans- and 13-cis-forms of retinal. retinal dehydrogenase RL00305 3-hydroxy-methylglutaryl coenzyme A cholesterol synthesis/the isoprenoid biosynthetic pathway 1.1.1.34 Mouse 10090 Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 16950652,1311272,6935624,4526203,15992608,6973393, The rate-limiting enzyme of cholesterol synthesis, beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (EC 1.1.1.34), is lowered to 45% 48 hr after removal of theophylline[6935624]#Mevinolin is known to inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (EC 1.1.1.34), the rate-limiting step in cholesterol biosynthesis[1311272]#We also observed that DnaJA4 overexpression increased the activity and the protein content of HMG-CoA reductase, the rate limiting enzyme in this pathway[16950652]#The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is the rate-limiting enzyme in cholesterol synthesis and is highly regulated by a variety of factors[15992608]#Some of these oxidation products are known to be generated spontaneously from cholesterol, which in itself is not affecting the activity of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34)[6973393]# The enzyme is inactivated by EC 2.7.11.31 {[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase} and reactivated by EC 3.1.3.47 {[hydroxymethylglutaryl-CoA reductase (NADPH)]-phosphatase}. hydroxymethylglutaryl-CoA reductase (NADPH) RL00306 arylalkylamine N-acetyltransferase melatonin synthesis 2.3.1.87 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 10329462, Presently, we find the expression of the serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT) mRNA, the rate-limiting enzyme in the conversion of serotonin to melatonin, in the rat suprachiasmatic nucleus (SCN) which contains the biological circadian clock in mammals[10329462]# Narrow specificity towards 2-arylethylamines, including serotonin (5-hydroxytryptamine), tryptamine, 5-methoxytryptamine and phenylethylamine. This is the penultimate enzyme in the production of melatonin (5-methoxy-N-acetyltryptamine) and controls its synthesis (cf. EC 2.1.1.4, acetylserotonin O-methyltransferase). Differs from EC 2.3.1.5 arylamine N-acetyltransferase. aralkylamine N-acetyltransferase RL00307 alcohol dehydrogenase alcohol oxidation 1.1.1.1 Rat 10116 Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350#Metabolism:Xenobiotics Biodegradation and Metabolism:3-Chloroacrylic acid degradation:map00641#Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Metabolism:Xenobiotics Biodegradation and Metabolism:1- and 2-Methylnaphthalene degradation:map00624#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 1096557,4038269,2932116,6370140,6356161, Since the electron flux in the respiratory chain is controlled by the ADP supply, alcohol dehydrogenase-dependent ethanol metabolism can be activated by perturbations which circumvent the rate-limiting step, such as artificial electron acceptors, gluconeogenic precursors, and uncoupling agents[1096557]#Rates of exchange catalysed by alcohol dehydrogenase were determined in vivo in order to find rate-limiting steps in ethanol metabolism[4038269]#These results suggest that ethanol oxidation by cytosolic alcohol dehydrogenase may be regulated in part by the hepatic acetaldehyde concentration achieved during ethanol metabolism rather than NADH reoxidation, either to supply NAD for the dehydrogenase, or to reduce inhibition of the enzyme by NADH, being a rate-limiting factor in ethanol metabolism in fasted rats.[2932116]#At ethanol concentrations above 10 mM, substrate inhibition, consistent with the formation a dead-end ADH-NADH-ethanol complex, also becomes a rate-limiting factor[6356161]#Qualitatively, therefore, alcohol dehydrogenase activity appears to be a major rate-limiting factor in ethanol metabolism[6370140]# A zinc protein. Acts on primary or secondary alcohols or hemi-acetals; the animal, but not the yeast, enzyme acts also on cyclic secondary alcohols. alcohol dehydrogenase RL00308 cyclopropane fatty acid synthase formation of cyclopropane rings on unsaturated fatty acids 2.1.1.79 E.coli 83333 15491158, Isotope and elemental effects indicate a rate-limiting methyl transfer as the initial step in the reaction catalyzed by Escherichia coli cyclopropane fatty acid synthase[15491158]# The enzyme adds a methylene group across the 9,10 position of a Delta9-olefinic acyl chain in phosphatidylethanolamine or, more slowly, phosphatidylglycerol or phosphatidylinositol, forming a cyclopropane derivative (cf. EC 2.1.1.16 methylene-fatty-acyl-phospholipid synthase). cyclopropane-fatty-acyl-phospholipid synthase RL00309 oxoglutarate dehydrogenase complex citric acid cycle 1.2.4.2/2.3.1.61/1.8.1.4 Yeast 4932 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 502909, Apparently, the deceleration of growth is due to a decrease in the activity of a thiamine-dependent enzyme (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase or transketolase) which is a limiting point of biosynthetic processes[502909]# A multimer (24-mer) of this enzyme forms the core of the multienzyme complex, and binds tightly both EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively succinylated by EC 1.2.4.2, and the only observed direction catalysed by EC 2.3.1.61 is that where this succinyl group is passed to coenzyme A. dihydrolipoyllysine-residue succinyltransferase RL00311 phospholipid n methyltransferase I Conversion of PE to PME and PME to PC in the presence of S-adenosyl-L-methionine/catecholamine pathway and production of epinephrine 2.1.1.17 Rat 10116 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 8207329,9380436, Conversion of PE to PME and PME to PC in the presence of S-adenosyl-L-methionine (SAM) are catalyzed by two phospholipid N-methyltransferases, PMT I and PMT II, of which PMT I is the rate limiting enzyme[8207329]#The enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) catalyze the rate-limiting step in the catecholamine pathway and production of epinephrine, respectively[9380436]# phosphatidylethanolamine N-methyltransferase RL00312 glucose-6-phosphate dehydrogenase pentose phosphate pathway (PPP)/the GSH- and NADPH-dependent H(2)O(2) elimination by PC12 cells/NADPH production 1.1.1.49 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030# 10098886, Treatment of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/ml) increased mRNA expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the pentose phosphate pathway (PPP), in a time-dependent fashion (0-24 h)[10098886]# Also acts slowly on beta-D-glucose and other sugars. Certain preparations reduce NAD+ as well as NADP+. glucose-6-phosphate dehydrogenase RL00313 Glucokinase glucose metabolis 2.7.1.2 Mouse 10090 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Human Diseases:Metabolic Disorders:Maturity onset diabetes of the young:map04950#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 8751724,16186394,7665557, Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver[8751724]#Glucokinase catalyzes a rate-limiting step in glucose metabolism in hepatocytes and pancreatic beta cells and is considered the "glucose sensor" for regulation of insulin secretion[7665557]#As the rate-limiting controller of glucose metabolism, glucokinase represents the primary beta-cell "glucose sensor." Inactivation of both glucokinase (GK) alleles results in permanent neonatal diabetes; inactivation of a single allele causes maturity-onset diabetes of the young type 2 (MODY-2)[16186394]# A group of enzymes found in invertebrates and microorganisms that are highly specific for glucose. glucokinase RL00314 Tryptophan hydroxylase the biosynthesis of serotonin (5-HT)/ melatonin biosynthesis 1.14.16.4 Mouse 10090 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 17666043,18082956,17675372,17727633,17613521, We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis[17666043]#Tryptophan hydroxylase 2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain[18082956]#Serotonin [5-hydroxytryptamine (5-HT)] biosynthesis depends on two rate-limiting tryptophan hydroxylases (Tph): Tph1, which is expressed in peripheral organs, and Tph2, which is expressed in neurons[17675372]#Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in raphe serotonin biosynthesis, and polymorphisms of TPH2 are implicated in vulnerability to psychiatric disorders[17613521]#Tryptophan hydroxylase (TPH) is the initial and rate-limiting enzyme in the biosynthesis of serotonin[17727633]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by a Ca2+-activated protein kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tryptophan 5-monooxygenase RL00315 ornithine decarboxylase polyamine metabolism 4.1.1.17 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 10320037, Ornithine decarboxylase (ODC) activity, the rate limiting step of polyamine synthesis, and levels of the diamine putrescine, the product of ornithine decarboxylase reaction, were analyzed in control (non-laminectomized) animals and at 2 and 4 h after laminectomy or compression injury at the L4 segmental level[10320037]# A pyridoxal-phosphate protein. ornithine decarboxylase RL00316 DXP synthase synthesis of isopentenyl pyrophosphate 2.2.1.7 E.coli 83333 Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 15898075, DXP (1-deoxy-D-xylulose-5-phosphate) synthase is encoded by dxs and participates in the rate-limiting step in the synthesis of isopentenyl pyrophosphate (IPP), a building block of lycopene[15898075]# Requires thiamine diphosphate. The enzyme forms part of an alternative nonmevalonate pathway for terpenoid biosynthesis (for diagram, click here). 1-deoxy-D-xylulose-5-phosphate synthase RL00317 acetyl CoA carboxylase the de novo synthesis of lipids and cholesterol 6.4.1.2 Rat 10116 Metabolism:Biosynthesis of Secondary Metabolites:Tetracycline biosynthesis:map00253#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 11978655,11485560,11205884,12065578, Because acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG[11978655]#We studied the effect of troglitazone treatment on rat liver acetyl-CoA carboxylase (ACC), the key enzyme that catalyzes the formation of malonyl-CoA, the rate-limiting step in the synthesis of long chain fatty acids[11205884]#The enzyme acetyl-CoA carboxylase alpha (ACC-alpha) is rate-limiting for the synthesis of long-chain fatty acids de novo[11485560]#Changes in the concentration of malonyl-CoA in many tissues have been related to alterations in the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in its formation[12065578]# A biotinyl-protein. Also catalyses transcarboxylation; the plant enzyme also carboxylates propanonyl-CoA and butanoyl-CoA. acetyl-CoA carboxylase RL00318 arylalkylamine N-acetyltransferase melatonin synthesis 2.3.1.87 Mouse 10090 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 15773915, In this study, we investigated their function using mouse pineal glands, and found that expression of the arylalkylamine N-acetyltransferase (Aa-Nat, EC 2.3.1.87, the rate-limiting enzyme of melatonin synthesis) gene after adrenergic receptor stimulation depended on the time of day even in vitro (gating)[15773915]# Narrow specificity towards 2-arylethylamines, including serotonin (5-hydroxytryptamine), tryptamine, 5-methoxytryptamine and phenylethylamine. This is the penultimate enzyme in the production of melatonin (5-methoxy-N-acetyltryptamine) and controls its synthesis (cf. EC 2.1.1.4, acetylserotonin O-methyltransferase). Differs from EC 2.3.1.5 arylamine N-acetyltransferase. aralkylamine N-acetyltransferase RL00319 ethanolamine kinase biosynthesis of phosphatidylethanolamine 2.7.1.82 Rat 10116 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 475777, This flux change was used to test the possible regulatory roles of ethanolamine kinase and of phosphoethanolamine cytidylyltransferase, which are rate-limiting enzymes of the cytidine pathway for the synthesis of phosphatidylethanolamine [Infante (1977) Biochem[475777]# ethanolamine kinase RL00320 carbamoyl phosphate synthase the de novo UTP biosynthetic pathway 6.3.5.5 Mouse 10090 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 7916269, Appearance of CAD activity, the rate-limiting enzyme for pyrimidine biosynthesis, as B cells progress into and through the G1 stage of the cell cycle[7916269]# The product carbamoyl phosphate is an intermediate in the biosynthesis of arginine and the pyrimidine nucleotides [4]. The enzyme from Escherichia coli has three separate active sites, which are connected by a molecular tunnel that is almost 100 A in length [8]. The amidotransferase domain within the small subunit of the enzyme hydrolyses glutamine to ammonia via a thioester intermediate. The ammonia migrates through the interior of the protein, where it reacts with carboxy phosphate to produce the carbamate intermediate. The carboxy-phosphate intermediate is formed by the phosphorylation of bicarbonate by ATP at a site contained within the N-terminal half of the large subunit. The carbamate intermediate is transported through the interior of the protein to a second site within the C-terminal half of the large subunit, where it is phosphorylated by another ATP to yield the final product, carbamoyl phosphate [6]. carbamoyl-phosphate synthase (glutamine-hydrolysing) RL00321 adenylate kinase DNA synthesis 2.7.4.3 E.coli 83333 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 15941717, The rate of DNA synthesis after infection of an ndk mutant was found to be about 40% of the rate seen in wild-type infection, implying that complementation of the missing NDP kinase function by adenylate kinase is fairly efficient, but that adenylate kinase becomes rate-limiting for DNA synthesis when it is the sole source of dNTPs[15941717]# Inorganic triphosphate can also act as donor. adenylate kinase RL00323 prolyl cis trans isomerase protein-folding 5.2.1.8 E.coli 83333 Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Genetic Information Processing:Folding, Sorting and Degradation:Ubiquitin mediated proteolysis:map04120# 18498364,12119099, Peptidyl-prolyl cis-trans isomerization is known to be a rate-limiting step in protein-folding and is slower at low temperature[12119099]# The first type of this enzyme found [1] proved to be the protein cyclophilin, which binds the immunosuppressant cyclosporin A. Other distinct families of the enzyme exist, one being FK-506 binding proteins (FKBP) and another that includes parvulin from Escherichia coli. The three families are structurally unrelated and can be distinguished by being inhibited by cyclosporin A, FK-506 and 5-hydroxy-1,4-naphthoquinone, respectively. peptidylprolyl isomerase RL00325 oxoglutarate dehydrogenase complex citric acid cycle 1.2.4.2/2.3.1.61/1.8.1.4 E.coli 83333 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 17367808, The thiamine-dependent E1o component (EC 1.2.4.2) of the 2-oxoglutarate dehydrogenase complex catalyses a rate-limiting step of the tricarboxylic acid cycle (TCA) of aerobically respiring organisms[17367808]# A multimer (24-mer) of this enzyme forms the core of the multienzyme complex, and binds tightly both EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively succinylated by EC 1.2.4.2, and the only observed direction catalysed by EC 2.3.1.61 is that where this succinyl group is passed to coenzyme A. dihydrolipoyllysine-residue succinyltransferase RL00326 P450scc steroid synthesis 1.14.15.6 Mouse 10090 Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 10964798, StAR protein mediates the rate-limiting and acutely regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane where the cytochrome P450 side chain cleavage (P450scc) enzyme initiates the synthesis of all steroid hormones[10964798]# A heme-thiolate protein. The reaction proceeds in three stages, with hydroxylation at C-20 and C-22 preceding scission of the side-chain at C-20. cholesterol monooxygenase (side-chain-cleaving) RL00327 hormone-sensitive lipase cholesteryl ester and diacylglycerol hydrolysis/lipolysis/intracellular TG hydrolysis 3.1.1.79 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910# 10832769,11691879, OBJECTIVE: The hormone-sensitive lipase (HSL) is the rate-limiting enzyme in adipose tissue lipolysis[10832769]#The rate-limiting step in adipose tissue lipolysis is catalysed by the enzyme hormone-sensitive lipase (HSL)[11691879]# This enzyme is a serine hydrolase. Compared with other lipases, hormone-sensitive lipase has a uniquely broad substrate specificity. It hydrolyses all acylglycerols (triacylglycerol, diacylglycerol and monoacylglycerol) [2,3,4] as well as cholesteryl esters [2,4], steroid fatty acid esters [5], retinyl esters [6] and p-nitrophenyl esters [4,7]. It exhibits a preference for the 1- or 3-ester bond of its acylglycerol substrate compared with the 2-ester bond [8]. The enzyme shows little preference for the fatty acids in the triacylglycerol, although there is some increase in activity with decreasing chain length. The enzyme activity is increased in response to hormones that elevate intracellular levels of cAMP. hormone-sensitive lipase RL00328 hormone-sensitive lipase cholesteryl ester and diacylglycerol hydrolysis/lipolysis/intracellular TG hydrolysis 3.1.1.79 Mouse 10090 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910# 11246809, Translocation of hormone-sensitive lipase, the rate-limiting enzyme of lipolysis, to the lipid droplet seems to be an important step during lipolytic activation[11246809]# This enzyme is a serine hydrolase. Compared with other lipases, hormone-sensitive lipase has a uniquely broad substrate specificity. It hydrolyses all acylglycerols (triacylglycerol, diacylglycerol and monoacylglycerol) [2,3,4] as well as cholesteryl esters [2,4], steroid fatty acid esters [5], retinyl esters [6] and p-nitrophenyl esters [4,7]. It exhibits a preference for the 1- or 3-ester bond of its acylglycerol substrate compared with the 2-ester bond [8]. The enzyme shows little preference for the fatty acids in the triacylglycerol, although there is some increase in activity with decreasing chain length. The enzyme activity is increased in response to hormones that elevate intracellular levels of cAMP. hormone-sensitive lipase RL00329 phospholipase a2 eicosanoid synthesis/arachidonic acid release and subsequent eicosanoid formation/prostaglandin synthesis 3.1.1.4 Rat 10116 Cellular Processes:Immune System:Fc epsilon RI signaling pathway:map04664#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592#Environmental Information Processing:Signal Transduction:MAPK signaling pathway:map04010#Environmental Information Processing:Signal Transduction:VEGF signaling pathway:map04370#Cellular Processes:Nervous System:Long-term depression:map04730#Cellular Processes:Endocrine System:GnRH signaling pathway:map04912# 10482042, In view of the potential role of prostaglandins (PGs) in development of glomerular hyperfiltration leading to diabetic nephropathy, we studied the temporal relationship of the activity of cytosolic phospholipase A2 (cPLA2), a rate-limiting enzyme for eicosanoid biosynthesis, with hyperfiltration and the histological changes in glomeruli using OLETF rats, a model for non-insulin-dependent diabetes mellitus (NIDDM)[10482042]# Also acts on phosphatidylethanolamine, choline plasmalogen and phosphatides, removing the fatty acid attached to the 2-position. Requires Ca2+. phospholipase A2 RL00330 phospholipase a2 eicosanoid synthesis/arachidonic acid release and subsequent eicosanoid formation/prostaglandin synthesis 3.1.1.4 Mouse 10090 Cellular Processes:Immune System:Fc epsilon RI signaling pathway:map04664#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592#Environmental Information Processing:Signal Transduction:MAPK signaling pathway:map04010#Environmental Information Processing:Signal Transduction:VEGF signaling pathway:map04370#Cellular Processes:Nervous System:Long-term depression:map04730#Cellular Processes:Endocrine System:GnRH signaling pathway:map04912# 106389, Activatable cellular phospholipase A2 (PLase; phosphatide 2-acyl-hydrolase, EC 3.1.1.4) has been proposed to constitute the first and rate-limiting step in prostaglandin synthesis and to regulate membrane function by altering the levels in the membrane of the detergent lipids lysolecithin and free fatty acids[106389]# Also acts on phosphatidylethanolamine, choline plasmalogen and phosphatides, removing the fatty acid attached to the 2-position. Requires Ca2+. phospholipase A2 RL00332 gamma-glutamylcysteine synthetase(gamma-GCShs) glutathione synthesis 6.3.2.2 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 10349842, In glial cells, incubation with 6-OHDA and H2O2 induced a significant increase in the expression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which correlated well with increased TPA-response element (TRE)-binding activity[10349842]# Can use L-aminohexanoate in place of glutamate. glutamate---cysteine ligase RL00333 gamma-glutamylcysteine synthetase(gamma-GCShs) glutathione synthesis 6.3.2.2 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 14500406,16081425, Glutamate cysteine ligase (GCL), which synthesizes gamma-glutamyl-cysteine (gamma-GC), is the rate-limiting enzyme in GSH biosynthesis[16081425]#Glutamate cysteine ligase, the rate-limiting enzyme for the synthesis of glutathione, represents an important component of chemoprevention paradigms[14500406]# Can use L-aminohexanoate in place of glutamate. glutamate---cysteine ligase RL00334 acetyl CoA carboxylase the de novo synthesis of lipids and cholesterol 6.4.1.2 Yeast 4932 Metabolism:Biosynthesis of Secondary Metabolites:Tetracycline biosynthesis:map00253#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 10757783, We report that mutants with conditional defects in the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase (ACC1), display unusually multilobed vacuoles, similar to those observed in vac8 mutant cells[10757783]# A biotinyl-protein. Also catalyses transcarboxylation; the plant enzyme also carboxylates propanonyl-CoA and butanoyl-CoA. acetyl-CoA carboxylase RL00335 glutathione s transferase arsenic biotransformation 2.5.1.18 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 15960885,10751553, RT-PCR data showed that the mRNA levels of gammaGCS, the rate-limiting enzyme of gamma-L-glutamyl-L-cysteinylglycine (GSH) synthesis, were increased by 6-OHDA after treatment for 24 h and 48 h; the mRNA levels of GPx, GR, and GST did not alter in 6-OHDA-treated astrocytes after treatment for 24 h and 48 h; and 6-OHDA increased the mRNA levels and the activity of gammaGT after treatment for 48 h, which induced a decrease in GSx levels, despite the up-regulation of gammaGCS after exposure to 6-OHDA for 48 h[15960885]#gamma-Glutamylcysteine synthetase (gamma-GCS) is a rate-limiting enzyme in the de novo synthesis of glutathione, a known scavenger of electrophiles and reactive oxygen species (ROS)[10751553]# A group of enzymes of broad specificity. R may be an aliphatic, aromatic or heterocyclic group; X may be a sulfate, nitrile or halide group. Also catalyses the addition of aliphatic epoxides and arene oxides to glutathione, the reduction of polyol nitrate by glutathione to polyol and nitrile, certain isomerization reactions and disulfide interchange. glutathione transferase RL00336 uroporphyrinogen synthase porphyrin synthesis 2.5.1.61 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 9460994, These observations of an associated response of PBGD and PPIX imply that PBGD may be a rate-limiting determinant for the efficacy of delta-ALA-induced photosensitization when used in photodynamic therapy[9460994]# The enzyme works by stepwise addition of pyrrolylmethyl groups until a hexapyrrole is present at the active centre. The terminal tetrapyrrole is then hydrolysed to yield the product, leaving a cysteine-bound dipyrrole on which assembly continues. In the presence of a second enzyme, EC 4.2.1.75 uroporphyrinogen-III synthase, which is often called cosynthase, the product is cyclized to form uroporphyrinogen-III. If EC 4.2.1.75 is absent, the hydroxymethylbilane cyclizes spontaneously to form uroporphyrinogen I. hydroxymethylbilane synthase RL00337 oxoglutarate dehydrogenase complex citric acid cycle 1.2.4.2/2.3.1.61/1.8.1.4 Rat 10116 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 14515360,7155797,6778477, Diminished activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme of the Krebs cycle, occurs in these disorders and may underlie decreased brain metabolism[14515360]#Oxoglutarate dehydrogenase shows the lowest activities along the whole nephron and appears to catalyze the rate-limiting step of the tricarboxylic acid cycle[7155797]#NAD+-isocitrate dehydrogenase and oxoglutarate dehydrogenase appeared to be rate-limiting in the oxidation of threo-Ds-isocitrate and oxoglutarate by uncoupled mitochondria from brown adipose tissue of cold-adapted rats[6778477]# A multimer (24-mer) of this enzyme forms the core of the multienzyme complex, and binds tightly both EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively succinylated by EC 1.2.4.2, and the only observed direction catalysed by EC 2.3.1.61 is that where this succinyl group is passed to coenzyme A. dihydrolipoyllysine-residue succinyltransferase RL00338 enoyl ACP reductase the elongation of unsaturated fatty acids 1.3.1.9 E.coli 83333 Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 17095231,8075395, Among them, FabI is an enoyl-ACP reductase which catalyzes the final and rate-limiting step of bacterial FAS[17095231]#coli strains with the hybrid FAS system unexpectedly revealed that enoyl-ACP reductase catalyses a rate-limiting step in the elongation of unsaturated fatty acids[8075395]# Catalyses the reduction of enoyl-acyl-[acyl-carrier-protein] derivatives of carbon chain length from 4 to 16. enoyl-[acyl-carrier-protein] reductase (NADH) RL00339 glutathione s transferase arsenic biotransformation 2.5.1.18 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 15761769, GSTO1, a member of the glutathione S-transferase superfamily omega, has recently been shown to be identical to the rate-limiting enzyme, monomethyl arsenous (MMA(V)) reductase which catalyzes methylarsonate (MMA(V)) to methylarsenous acid (MMA(III)) during arsenic biotransformation[15761769]# A group of enzymes of broad specificity. R may be an aliphatic, aromatic or heterocyclic group; X may be a sulfate, nitrile or halide group. Also catalyses the addition of aliphatic epoxides and arene oxides to glutathione, the reduction of polyol nitrate by glutathione to polyol and nitrile, certain isomerization reactions and disulfide interchange. glutathione transferase RL00340 acyl CoA oxidase very-long-chain fatty acid peroxisomal oxidation 1.3.3.6 Mouse 10090 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592# 11855929,10672038,8798738,12576521,8934448, Straight-chain acyl-CoA oxidase (AOX) catalyzes the first, rate-limiting step of peroxisomal beta-oxidation of very-long-chain saturated and unsaturated fatty acids[11855929]#The biologic role of peroxisomal beta-oxidation system, which consists of three enzymes: fatty acyl-CoA oxidase (ACOX), enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), and thiolase, has been examined in mice by disrupting ACOX gene, which encodes the first and rate-limiting enzyme of this system[8798738]#Straight-chain acyl-CoA oxidase is the first and rate limiting enzyme in the peroxisomal beta-oxidation pathway catalysing the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, thereby producing H2O2[10672038]#Our results show that in healthy mice a low dietary DHA dose (< 0.2%; this corresponds to a dose prescribed to peroxisomal patients) has no effect on several hepatic peroxisomal H2O2-producing enzymes, including the rate-limiting enzyme of the peroxisomal fatty acid beta-oxidation[8934448]#Etomoxir administration for 1 day significantly increased (4.4-fold induction) the mRNA expression of acyl-CoA oxidase (ACO), which catalyzes the rate-limiting step in peroxisomal beta-oxidation[12576521]# A flavoprotein (FAD). Acts on CoA derivatives of fatty acids with chain lengths from 8 to 18. acyl-CoA oxidase RL00341 biotin synthase biotin biosynthesis 2.8.1.6 Yeast 4932 Metabolism:Metabolism of Cofactors and Vitamins:Biotin metabolism:map00780# 16195795, utilis biotin synthase (BIO2) gene, the gene of the rate-limiting enzyme for biotin biosynthesis, and assembled it under the control of a strong promoter[16195795]# This single-turnover enzyme is a member of the 'AdoMet radical ' (radical SAM) family, all members of which produce the 5'-deoxyadenosin-5'-yl radical and methionine from AdoMet [i.e. S-adenosylmethionine, or S-(5'-deoxyadenosin-5'-yl)methionine], by the addition of an electron from an iron-sulfur centre. The enzyme has both a [2Fe-2S] and a [4Fe-4S] centre, and the latter is believed to donate the electron. Two molecules of AdoMet are converted into radicals; these activate positions 6 and 9 of dethiobiotin by abstracting a hydrogen atom from each, and thereby forming 5'-deoxyadenosine. Sulfur insertion into dethiobiotin at C-6 takes place with retention of configuration [3]. The sulfur donor has not been identified to date --- it is neither elemental sulfur nor from AdoMet, but it may be from the [2Fe-2S] centre [4]. biotin synthase RL00342 phosphoserine phosphatase synthesis of serine 3.1.3.3 Rat 10116 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260# 8858931, The rate-limiting step in the synthesis of serine is the hydrolysis of phosphoserine by phosphoserine phosphatase (EC 3.1.3.3)[8858931]# phosphoserine phosphatase RL00343 Glutathione synthase biosynthesis of glutathione and phytochelatins 6.3.2.3 E.coli 83333 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 9880348, We conclude that in the presence of Cd, the GS enzyme is rate limiting for the biosynthesis of glutathione and phytochelatins, and that overexpression of GS offers a promising strategy for the production of plants with superior heavy-metal phytoremediation capacity[9880348]# glutathione synthase RL00344 P450scc steroid synthesis 1.14.15.6 Rat 10116 Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 10964264,8584034,10619400,9666348,16780839,15231695,16632873,12242026,11312650,11191081,16844298,9888540, Northern and slot blot hybridization analyses revealed that ovarian mRNA levels for cytochrome P450 side-chain cleavage, the rate-limiting enzyme in P synthesis, were markedly reduced in PE rats following hCG stimulation[10964264]#Regulation of steroidogenesis in classic endocrine tissues is mediated by transcriptional regulation of the P450scc gene, which encodes the first and rate-limiting cholesterol side-chain cleavage enzyme[8584034]#In the present study, we evaluate the effect of IGF-I on the gene expression and protein levels of steroidogenic acute regulatory protein (StAR), the rate-limiting step in steroidogenesis[9666348]#StAR mediates the rate-limiting step of steroidogenesis, which is the transfer of cholesterol to the inner mitochondrial membrane[10619400]#Here, we found that P450scc, the rate-limiting enzyme in steroid synthesis, is upregulated in hippocampal glia during the latent period after pilocarpine-induced SE in rats[16780839]#Herein, we demonstrate that culturing the aged cells with dibutyryl cAMP, a membrane-permeable cAMP agonist that bypasses the LH receptor-adenlyly cyclase cascade, restores testosterone production to levels comparable to those of young cells and also restores steroidogenic acute regulatory protein and P450scc, the proteins involved in the rate-limiting steps of steroidogenesis[15231695]#P450scc is the key enzyme catalyzing the conversion of cholesterol (CHOL) into PREG, the rate-limiting step in the biosynthesis of all classes of steroids[16632873]#These results support the hypothesis that NO inhibits the rate-limiting enzyme in steroidogenesis independent of GC-S activation[12242026]#In these studies, several structurally related phthalates (0-200 microM) and Wy-14,643 (0-100 microM) were compared to MEHP for their effects on granulosa cell estradiol production and transcript levels of cytochrome P450 enzyme CYP 19, also known as aromatase (P450arom), the rate-limiting enzyme in the conversion of androgens to estrogens[11312650]#The mRNA levels of Cyp11a - a rate-limiting enzyme in testosterone synthesis - positively correlated with the menaquinone-4 (MK-4) concentration in the testis[16844298]#However, because P450scc is reduced in old Leydig cells, the reaction catalyzed by this enzyme would be rate-limiting under circumstances in which saturating amounts of cholesterol entered the mitochondria[11191081]#There are two main regulatory sites of aldosterone biosynthesis, the early rate-limiting step by the P450scc and the final steps by the P450aldo[9888540]# A heme-thiolate protein. The reaction proceeds in three stages, with hydroxylation at C-20 and C-22 preceding scission of the side-chain at C-20. cholesterol monooxygenase (side-chain-cleaving) RL00345 Thymidylate synthase the synthesis of pyrimidine nucleotides 2.1.1.45 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:One carbon pool by folate:map00670#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 3709927, Activation energy for the reaction, catalyzed by thymidylate synthase from mouse tumour but not from mouse thymus, lowers at temperatures above 34 degrees C, reflecting a change of rate-limiting step in dTMP formation[3709927]# thymidylate synthase RL00346 squalene epoxidase sterol biosynthesis/cholesterol biogenesis 1.14.99.7 Rat 10116 Metabolism:Biosynthesis of Secondary Metabolites:Terpenoid biosynthesis:map00900#Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 11520216,11199136,10733917, Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C(1)-C(18)) esters of hexahydroxydiphenyl (HHDP) dicarboxylic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase, a rate-limiting enzyme of cholesterol biosynthesis[11520216]#n-Alkyl esters (ethyl, octyl, dodecyl, and cetyl) of gallic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase (SE), a rate-limiting enzyme of cholesterol biogenesis[10733917]#It was demonstrated for the first time that the cholesterol-lowering effect of rhubarb may be attributed to the potent inhibition activities of SE, a rate-limiting enzyme of cholesterol biogenesis.[11199136]# A flavoprotein (FAD). This enzyme, together with EC 5.4.99.7 lanosterol synthase, was formerly known as squalene oxidocyclase. squalene monooxygenase RL00347 argininosuccinic acid synthetase urea production/urea cycle 6.3.4.5 Rat 10116 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 1122920, Control experiments (sham-operated, starved rats) revealed that the activities of only two enzymes of the cycle are altered in the uraemic state: argininosuccinic acid synthetase (EC 6.3.4.5.), which is considered to be rate limiting for urea production and carbamyl phosphate synthetase (EC 2.7.2.5.)[1122920]# argininosuccinate synthase RL00348 argininosuccinic acid synthetase urea production/urea cycle 6.3.4.5 Mouse 10090 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 12672181, We investigated the induction of iNOS together with argininosuccinate synthase (AS) and GTP cyclohydrolase I (GTPCH), 2 of the rate-limiting enzymes for high output NO generation, in the Tg197 h-TNF-alpha transgenic model of arthritis[12672181]# argininosuccinate synthase RL00349 phosphofructokinase glycolysis 2.7.1.11 Mouse 10090 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 17595219,1828673, Intracellular distribution of cytoskeleton-bound and soluble phosphofructokinase (PFK) (the rate-limiting enzyme in glycolysis) in mdx dystrophic muscle was the same as in control nondystrophic muscle[1828673]# D-Tagatose 6-phosphate and sedoheptulose 7-phosphate can act as acceptors. UTP, CTP and ITP can act as donors. Not identical with EC 2.7.1.105 6-phosphofructo-2-kinase. 6-phosphofructokinase RL00350 galactosyltransferase uridine nucleotide cycle that supports lactose synthesis 2.4.1.22 Mouse 10090 Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 1908098, It is, therefore, apparent that the rate-limiting component for the PRL stimulation of lactose synthesis in cultured mouse mammary tissues is galactosyl transferase activity[1908098]# The enzyme is a complex of two proteins, A and B. In the absence of the B protein (alpha-lactalbumin), the enzyme catalyses the transfer of galactose from UDP-galactose to N-acetylglucosamine (EC 2.4.1.90 N-acetyllactosamine synthase). lactose synthase RL00351 Lipoprotein lipase the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism 3.1.1.34 Rat 10116 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10364085,11158876, Lipoprotein lipase (LpL) is the rate limiting enzyme for lipolysis of TG[11158876]#Vascular endothelium-bound lipoprotein lipase (LPL) is rate limiting for free fatty acid (FFA) transport into tissues[10364085]# Hydrolyses triacylglycerols in chylomicrons and low-density lipoproteins. Also hydrolyses diacylglycerol. lipoprotein lipase RL00352 Lipoprotein lipase the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism 3.1.1.34 Mouse 10090 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10077655, The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism[10077655]# Hydrolyses triacylglycerols in chylomicrons and low-density lipoproteins. Also hydrolyses diacylglycerol. lipoprotein lipase RL00353 cytochrome c oxidase oxidative phosphorylation 1.9.3.1 Rat 10116 Metabolism:Energy Metabolism:Oxidative phosphorylation:map00190# 12874793, COX is the only electron transport chain complex to display isoforms, consistent with its suggested rate-limiting role[12874793]# A cytochrome of the a type containing copper. The reduction of O2 to water is accompanied by the extrusion of four protons from the intramitochondrial compartment. Several bacteria appear to contain analogous oxidases. cytochrome-c oxidase RL00354 cytochrome c oxidase oxidative phosphorylation 1.9.3.1 Mouse 10090 Metabolism:Energy Metabolism:Oxidative phosphorylation:map00190# 12874793, COX is the only electron transport chain complex to display isoforms, consistent with its suggested rate-limiting role[12874793]# A cytochrome of the a type containing copper. The reduction of O2 to water is accompanied by the extrusion of four protons from the intramitochondrial compartment. Several bacteria appear to contain analogous oxidases. cytochrome-c oxidase RL00355 phosphoethanolamine cytidylyltransferase phosphatidylethanolamine synthesis 2.7.7.14 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 603639,475777,11097182, An analysis of the available data on the cytidine pathway for the synthesis of phosphatidylcholine and phosphatidylethanolamine, by the logic derived from the theoretical principles of metabolic regulation, shows that the first two reactions catalysed by choline (ethanolamine) kinase and phosphocholine (phosphoethanolamine) cytidylyltransferase are rate-limiting, whereas the phosphocholine (phosphoethanolamine) transferase step is near equilibrium in rat liver.[603639]#This flux change was used to test the possible regulatory roles of ethanolamine kinase and of phosphoethanolamine cytidylyltransferase, which are rate-limiting enzymes of the cytidine pathway for the synthesis of phosphatidylethanolamine [Infante (1977) Biochem[475777]#The activities of the rate-limiting enzymes in the de novo synthesis of PC and PE, CTP:phosphocholine cytidylyltransferase (CT), and CTP:phosphoethanolamine cytidylyltransferase (ET), respectively, were measured in the retinas excised at 5:00, 9:00, 13:00, and 17:00 h from rats adapted to a 24-h cycle with lights on from 7:00 to 19:00 h[11097182]# ethanolamine-phosphate cytidylyltransferase RL00357 phosphoribosyl pyrophosphate amidotransferase the purine de novo pathway 2.4.2.14 Rat 10116 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 6327016, The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# amidophosphoribosyltransferase RL00358 phosphoribosyl pyrophosphate amidotransferase the purine de novo pathway 2.4.2.14 Mouse 10090 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 6327016, The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# amidophosphoribosyltransferase RL00359 Stearoyl-CoA desaturase monounsaturated fatty acid synthesis,oleic acid synthesis, 1.14.19.1 Rat 10116 Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040# 10484602,10581155, A key enzyme involved in this process is the membrane-bound stearoyl-CoA desaturase (SCD) which is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids[10484602]#Stearoyl-CoA desaturase (SCD) is a key rate-limiting enzyme in the synthesis of unsaturated fatty acids by insertion of a cis-double bond in the Delta9 position of fatty acid substrates[10581155]# An iron protein. The rat liver enzyme is an enzyme system involving cytochrome b5 and EC 1.6.2.2, cytochrome-b5 reductase. The ferricytochrome b5 produced is reduced by NADH and cytochrome-b5 reductase (EC 1.6.2.2). stearoyl-CoA 9-desaturase RL00360 Stearoyl-CoA desaturase monounsaturated fatty acid synthesis,oleic acid synthesis, 1.14.19.1 Mouse 10090 Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040# 10484602,10581155, A key enzyme involved in this process is the membrane-bound stearoyl-CoA desaturase (SCD) which is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids[10484602]#Stearoyl-CoA desaturase (SCD) is a key rate-limiting enzyme in the synthesis of unsaturated fatty acids by insertion of a cis-double bond in the Delta9 position of fatty acid substrates[10581155]# An iron protein. The rat liver enzyme is an enzyme system involving cytochrome b5 and EC 1.6.2.2, cytochrome-b5 reductase. The ferricytochrome b5 produced is reduced by NADH and cytochrome-b5 reductase (EC 1.6.2.2). stearoyl-CoA 9-desaturase RL00362 Heme oxygenase CO generation,degrades heme/ production of bilirubin/ heme degradation pathway 1.14.99.3 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 10692503,10727990, Heme oxygenase (HO) catalyzes the rate-limiting enzymatic step of heme degradation and regulates the cellular heme content[10692503]#Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to biliverdin, carbon monoxide (CO), and free iron[10727990]# Requires NAD(P)H and EC 1.6.2.4, NADPH---hemoprotein reductase. The terminal oxygen atoms that are incorporated into the carbonyl groups of pyrrole rings A and B of biliverdin are derived from two separate oxygen molecules [4]. The third oxygen molecule provides the oxygen atom that converts the alpha-carbon to CO. The central iron is kept in the reduced state by NAD(P)H. heme oxygenase RL00363 acyl coA:cholesterol acyltransferase cholesterol esterification 2.3.1.26 Mouse 10090 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120# 16245952, Coinfection of mice with adenoviruses expressing human LCAT and the helix 6P mutant dramatically increased plasma HDL and apoA-I levels and converted the discoidal into spherical HDL, indicating that the LCAT activity was rate-limiting for the biogenesis of HDL[16245952]# The animal enzyme is highly specific for transfer of acyl groups with a single cis double bond that is nine carbon atoms distant from the carboxy group. sterol O-acyltransferase RL00364 hydroxy delta steroid dehydrogenase the sex steroid hormone biosynthesis pathway 1.1.1.145 Rat 10116 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 12782399,12441193, Hydroxyflutamide a specific androgen receptor (AR) antagonist, and cyproterone acetate or trilostane, both inhibitors of 3 beta-hydroxysteroid dehydrogenase/delta 4,5 isomerase, the rate-limiting enzyme for the conversion of DHEA to sex steroids, did not affect the ability of DHEA to downregulate GnRH gene expression[12782399]#We investigated the first step of the sex steroid hormone biosynthesis pathway by assaying the activities of 3 beta-hydroxy-delta 5-steroid dehydrogenase, the rate-limiting enzyme in this pathway[12441193]# Acts on 3beta-hydroxyandrost-5-en-17-one to form androst-4-ene-3,17-dione and on 3beta-hydroxypregn-5-en-20-one to form progesterone. 3beta-hydroxy-Delta5-steroid dehydrogenase RL00365 5'-nucleotidase transformation of AMP to adenosine 3.1.3.5 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Nicotinate and nicotinamide metabolism:map00760#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 17267736,17548651,17493587, Because ectoapyrase (CD39) and ecto-5'-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI[17548651]#Because ecto-5'-nucleotidase (CD73) is rate limiting for extracellular adenosine generation, this study examined the contribution of CD73-dependent adenosine production to ischemic preconditioning (IP) of the kidneys. [17267736]#The cytosolic deoxycytidine kinase (dCK; EC 2.7.1.74) and thymidine kinase (TK1; EC 2.7.1.21), the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK; EC 2.7.1.113) as well as 5'-deoxynucleotidases (5'-dNT; EC 3.1.3.5) are enzymes that control rate-limiting steps in formation of intracellular and intra-mitochondrial nucleotides[17493587]# Wide specificity for 5'-nucleotides. 5'-nucleotidase RL00366 pantothenate kinase coenzyme A ( CoA ) biosynthetic pathway 2.7.1.33 E.coli 83333 Metabolism:Metabolism of Cofactors and Vitamins:Pantothenate and CoA biosynthesis:map00770# 16701556, Pantothenate kinase (PanK), a key regulatory enzyme in the coenzyme A (CoA) biosynthetic pathway, catalyzes the rate-limiting phosphorylation of pantothenic acid to form phosphopantothenate during CoA biosynthesis[16701556]# pantothenate kinase RL00367 pantothenate kinase coenzyme A ( CoA ) biosynthetic pathway 2.7.1.33 Yeast 4932 Metabolism:Metabolism of Cofactors and Vitamins:Pantothenate and CoA biosynthesis:map00770# 15176870,15843025, The acetyl-CoA levels also increased ( approximately 5-fold) but not as much as that of CoA, showing that the carbon flux from the pyruvate node is rate-limiting upon an increase in CoA levels[15176870]#Fms1 is a rate-limiting enzyme for the biosynthesis of pantothenic acid in yeast[15843025]# pantothenate kinase RL00368 tyrosine aminotransferase catabolic pathway of tyrosine 2.6.1.5 Mouse 10090 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400#Metabolism:Amino Acid Metabolism:Phenylalanine metabolism:map00360#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271#Metabolism:Biosynthesis of Secondary Metabolites:Novobiocin biosynthesis:map00401#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 1348057, In addition, biologically active NRF-1 sites are found in genes encoding the eukaryotic translation initiation factor 2 alpha-subunit and tyrosine aminotransferase, both of which participate in the rate-limiting step of their respective pathways of protein biosynthesis and tyrosine catabolism[1348057]# A pyridoxal-phosphate protein. L-Phenylalanine can act instead of L-tyrosine. The mitochondrial enzyme may be identical with EC 2.6.1.1 (aspartate transaminase). The three isoenzymic forms are interconverted by EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain). The enzyme can also catalyse the final step in the methionine-salvage pathway of Klebsiella pneumoniae [8]. tyrosine transaminase RL00369 ornithine decarboxylase polyamine metabolism 4.1.1.17 Yeast 4932 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 12054575, Ornithine decarboxylase (ODC), the first rate-limiting enzyme in the polyamine biosynthesis is one of the most rapidly degraded proteins in eukaryotic cells[12054575]# A pyridoxal-phosphate protein. ornithine decarboxylase RL00370 GTP cyclohydrolase 1 BH4 synthesis/the biosynthesis of tetrahydrobiopterin (BH(4)),a natural cofactor for tyrosine and tryptophan hydroxylases 3.5.4.16 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 18054268,17978343,17973864,18268143,17679617,18372436,17463333,18645049, We previously described that hydrogen peroxide (H(2)O(2)) increases BH4 levels through the induction of GTP-cyclohydrolase I (GTPCH), which is the rate-limiting enzyme for the synthesis of BH4, in vascular endothelial cells[18054268]#It has been reported that activation of the immune system stimulates an increase in endogenous BH4 rate-limiting enzyme GTP cyclohydrolase I (GTPCH I) activity, resulting in an increase in intracellular BH4 levels and BH4-dependent NO synthesis in various cells[17978343]#Guanosine 5'-triphosphate-cyclohydrolase I (GTPCH) is the first rate-limiting enzyme for de novo BH(4) synthesis[17973864]#Here, we demonstrate that diabetes reduced BH4 by increasing 26S proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I (GTPCH), a rate-limiting enzyme in the synthesis of BH4, in parallel with increased formation of both superoxide and peroxynitrite (ONOO-)[17679617]#GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for de novo BH4 synthesis[18268143]#GTP-cyclohydrolase 1 (GTP-CH1) catalyses the first and rate-limiting step for the de novo production of tetrahydrobiopterin (BH(4)), an essential cofactor for nitric oxide synthase (NOS)[18372436]#METHODS AND RESULTS: We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice[17463333]#GTP cyclohydrolase 1 (GTPCH1) is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase (eNOS) dictating, at least partly, the balance of NO and superoxide produced by this enzyme[18645049]# The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit; the recyclization may be non-enzymic. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 4.2.3.12 (6-pyruvoyltetrahydropterin synthase) [3]. GTP cyclohydrolase I RL00371 Beta-secretase generation of the amyloid beta-peptide (Abeta) in Alzheimer disease 3.4.23.46 Mouse 10090 Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010# 18393796,11816789,17156133,16306400,15987683,18695518,15452128, BACE1 exhibits all the properties of the beta-secretase, and as the key rate-limiting enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD[11816789]#Beta-secretase (BACE1) is the rate-limiting protease for the generation of the amyloid beta-peptide (Abeta) in Alzheimer disease[15987683]#Beta-secretase [beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the beta-amyloid (Abeta) peptide involved in the pathogenesis of Alzheimer's disease (AD)[16306400]#Amyloid-beta (Abeta) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase cleavage[15452128]#Beta-site APP cleaving enzyme-1 (BACE-1), is a rate-limiting enzyme for beta amyloid production[18695518]# Suggested to be the major "beta-secretase" responsible for the cleavage of the beta-amyloid precursor protein to form the amyloidogenic beta-peptide that is implicated in the pathology of Alzheimer's disease. In peptidase family A1 but is atypical in containing a C-terminal membrane-spanning domain. memapsin 2 RL00372 Aromatase estrogen biosynthesis 1.14.14.1 Mouse 10090 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Xenobiotics Biodegradation and Metabolism:gamma-Hexachlorocyclohexane degradation:map00361#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 10503904, Thus it is important to understanding how P450s participate in the carcinogenesis process and to determine if they are indeed the rate limiting and critical interface between the chemical and its biological activity[10503904]# A group of heme-thiolate proteins (P-450), acting on a wide range of substrates including many xenobiotics, steroids, fatty acids, vitamins and prostaglandins; reactions catalysed include hydroxylation, epoxidation, N-oxidation, sulfooxidation, N-, S- and O-dealkylations, desulfation, deamination, and reduction of azo, nitro and N-oxide groups. Together with EC 1.6.2.4, NADPH---hemoprotein reductase, it forms a system in which two reducing equivalents are supplied by NADPH. Some of the reactions attributed to EC 1.14.15.3, alkane 1-monooxygenase, belong here. unspecific monooxygenase RL00373 phosphatidylinositol phosphate kinase PA biosynthesis 2.7.1.68 Mouse 10090 Cellular Processes:Cell Motility:Regulation of actin cytoskeleton:map04810#Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562# 3027078, Direct measurements of the activities of PtdIns kinase and PtdIns-P kinase in freeze-thawed cells revealed that the activity of PtdIns kinase was rate-limiting for the synthesis of PtdIns-P2[3027078]# This enzyme can also phosphorylate PtdIns3P in the 4-position, and PtdIns, PtdIns3P and PtdIns(3,4)P2 in the 5-position in vitro, but to a lesser extent. The last of these reactions occurs in vivo and is physiologically relevant. Three different isoforms are known. 1-phosphatidylinositol-4-phosphate 5-kinase RL00374 acyl CoA oxidase very-long-chain fatty acid peroxisomal oxidation 1.3.3.6 Rat 10116 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Lipid Metabolism:Biosynthesis of unsaturated fatty acids:map01040#Metabolism:Lipid Metabolism:alpha-Linolenic acid metabolism:map00592# 12758125,15805059, Formalin-fixed, paraffin embedded liver sections from rats exposed to a Peroxisome Proliferator Activated Receptor (PPAR) agonist were stained with antibodies against peroxisomal targeting signal-1 (PTS-1) (a highly conserved tripeptide contained within all peroxisomal enzymes), Acyl CoA oxidase (AOX) (the rate limiting enzyme of peroxisomal beta oxidation), and catalase (an inducible peroxisomal antioxidant enzyme) to evaluate peroxisomal beta oxidation, oxidative stress, and peroxisome proliferation[15805059]#In the present study, the cloning, expression and characterization of the rate-limiting enzyme of the peroxisomal beta-oxidation spiral, acyl CoA oxidase (AOX), from koala (Phascolarctos cinereus) liver is described[12758125]# A flavoprotein (FAD). Acts on CoA derivatives of fatty acids with chain lengths from 8 to 18. acyl-CoA oxidase RL00375 Cathepsin B 3.4.22.1 Rat 10116 Cellular Processes:Immune System:Antigen processing and presentation:map04612# 7295740, Cathepsin B who acts as a rate-limiting enzyme in the degradation of aldolase[7295740]# An intracellular (lysosomal) enzyme in peptidase family C1 (papain family) cathepsin B RL00376 phosphatidate phosphohydrolase triacylglycerol(TG) synthesis/the de novo synthesis of lipids and cholesterol 3.1.3.4 Rat 10116 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600#Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 11678440,12359092,15539300,15975496,15527069, The OA-feeding significantly increased the activity of hepatic microsomal phosphatidate phosphohydrolase (PAP), which is the rate-limiting enzyme for TG synthesis[11678440]#In contrast, phosphatidate phosphohydrolase, the rate-limiting enzyme for TG synthesis, was found to be 20% lower in the livers of the CLA-fed rats[12359092]#The activity of hepatic microsomal phosphocholine cytidyltransferase (the rate-limiting enzyme in phosphatidylcholine synthesis) was reduced significantly by L-NNA[15539300]#Further, a significant increase in the activity of carnitine palmitoyl transferase, a rate-limiting enzyme of fatty acid beta-oxidation, was found in the PC+OA group[15975496]#These results were attributed to the significant increases in the activities of phosphatidate phosphohydrolase (PAP), a rate-limiting enzyme of TG synthesis, and glucose-6-phosphate dehydrogenase, a fatty acid synthesis-related enzyme[15527069]# phosphatidate phosphatase RL00377 choline kinase biosynthesis of phosphatidylcholine 2.7.1.32 Rat 10116 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 217369,3365445, Choline kinase and phosphocholine cytidylytransferase catalyse the rate-limiting steps of the cytidine pathway for the synthesis of phosphatidylcholine [Infante (1977) Biochem[217369]#The results indicated that in rat platelets, PC synthesis occurred mainly via the CDP-choline pathway, and suggested that CTP:phosphocholine cytidylyltransferase was the rate-limiting step; they also indicated that the activity of this enzyme and that of choline kinase might be enhanced in SHR platelets compared to Wistar-Kyoto rat (WKY) platelets, and may thus be responsible for the enhanced PC synthesis[3365445]# Ethanolamine and its methyl and ethyl derivatives can also act as acceptors. choline kinase RL00378 pyruvate dehydrogenase acetyl coenzyme A synthesis/synthesis of acetylcholine 1.2.4.1 Rat 10116 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine biosynthesis:map00290#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 10720420, The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation[10720420]# Contains thiamine diphosphate. It is a component (in multiple copies) of the multienzyme pyruvate dehydrogenase complex in which it is bound to a core of molecules of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, which also binds multiple copies of EC 1.8.1.4, dihydrolipoyl dehydrogenase. It does not act on free lipoamide or lipoyllysine, but only on the lipoyllysine residue in EC 2.3.1.12. pyruvate dehydrogenase (acetyl-transferring) RL00379 tyrosine aminotransferase catabolic pathway of tyrosine 2.6.1.5 Rat 10116 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400#Metabolism:Amino Acid Metabolism:Phenylalanine metabolism:map00360#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271#Metabolism:Biosynthesis of Secondary Metabolites:Novobiocin biosynthesis:map00401#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 1526942, The major differences between the flight group and the synchronous control were elevations in microsomal protein, liver glycogen content, tyrosine aminotransferase, and tryptophan oxygenase and reductions in sphingolipids and the rate-limiting enzyme of heme biosynthesis, delta-aminolevulinic acid synthase[1526942]# A pyridoxal-phosphate protein. L-Phenylalanine can act instead of L-tyrosine. The mitochondrial enzyme may be identical with EC 2.6.1.1 (aspartate transaminase). The three isoenzymic forms are interconverted by EC 3.4.22.32 (stem bromelain) and EC 3.4.22.33 (fruit bromelain). The enzyme can also catalyse the final step in the methionine-salvage pathway of Klebsiella pneumoniae [8]. tyrosine transaminase RL00381 NAD dependent isocitrate dehydrogenase tricarboxylic acid cycle 1.1.1.41 Yeast 4932 Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 8626605, Mitochondrial NAD-dependent isocitrate dehydrogenase catalyzes a rate-limiting step in the tricarboxylic acid cycle[8626605]# Requires Mn2+ or Mg2+ for activity. Unlike EC 1.1.1.42, isocitrate dehydrogenase (NADP+), oxalosuccinate cannot be used as a substrate. In eukaryotes, isocitrate dehydrogenase exists in two forms: an NAD+-linked enzyme found only in mitochondria and displaying allosteric properties, and a non-allosteric, NADP+-linked enzyme that is found in both mitochondria and cytoplasm [7]. The enzyme from some species can also use NADP+ but much more slowly [9]. isocitrate dehydrogenase (NAD+) RL00382 acetylcholinesterase acylation with certain substrates precedes general acid-base catalysis 3.1.1.7 Rat 10116 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 15936353, To better understand the mechanisms of their modulatory effects and also other effects on the cholinergic system in the brain, the activities of ACh hydrolyzing enzyme acetylcholinesterase (AChE), ACh synthesizing enzyme choline acetyltransferase (ChAT) and ACh synthesizing rate-limiting step, high-affinity choline uptake (HACU) were examined in the present study[15936353]# Acts on a variety of acetic esters; also catalyses transacetylations. acetylcholinesterase RL00383 acetylcholinesterase acylation with certain substrates precedes general acid-base catalysis 3.1.1.7 Mouse 10090 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 12415870, Measurements of the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), enzymes that hydrolyze and synthesize acetylcholine (ACh) and high-affinity choline uptake (HACU), a rate-limiting step in the synthesis of ACh, were determined in the presence of various concentrations of sodium azide in vitro[12415870]# Acts on a variety of acetic esters; also catalyses transacetylations. acetylcholinesterase RL00384 steroid alpha reductase the production of 5 alpha-reduced steroids 1.3.99.5 Rat 10116 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Human Diseases:Cancers:Prostate cancer:map05215# 7588289,11408363, Steroid 5 alpha-reductase is the rate-limiting enzyme in the production of 5 alpha-reduced steroids in many tissues[7588289]#These findings confirm the role of 5alpha-reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7alpha- and 11-position of the steroid skeleton on 5alpha-reduction[11408363]# 3-oxo-5alpha-steroid 4-dehydrogenase RL00385 pyruvate dehydrogenase complex tricarboxylic acid cycle 1.2.4.1/2.3.1.12/1.8.1.4 E.coli 83333 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine biosynthesis:map00290#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 11401572,3516150, Both transient and steady state characteristics of the mutant are presented and show in contrast to the wild-type enzyme where a rearrangement of an enzyme-NADH-pyruvate complex is rate-limiting that in the mutant the rearrangement is much faster and hydride transfer is the first slow step[11401572]#We have now determined that if the reactions catalyzed by E3 are made rate-limiting, the excess E3 functions equivalently to that in the native complex.[3516150]# A multimer (24-mer or 60-mer, depending on the source) of this enzyme forms the core of the pyruvate dehydrogenase multienzyme complex, and binds tightly both EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively acetylated by EC 1.2.4.1, and the only observed direction catalysed by EC 2.3.1.12 is that where the acetyl group is passed to coenzyme A. dihydrolipoyllysine-residue acetyltransferase RL00386 carbamoyl phosphate synthase the de novo UTP biosynthetic pathway 6.3.5.5 Rat 10116 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 3812736,7608487, Assuming that plasma NH3 levels reflect those in mitochondria, the NH3 concentration yielding half-maximal rates of urea synthesis (close to 2 microM) was in the same range as Km for the rate-limiting step in ureagenesis, carbamoyl phosphate synthetase (EC 6.3.4.16)[3812736]#The data indicate that the expression of urea cycle enzymes, in particular that of carbamoyl phosphate synthetase which is the rate-limiting step, is up-regulated by partial hepatectomy[7608487]# The product carbamoyl phosphate is an intermediate in the biosynthesis of arginine and the pyrimidine nucleotides [4]. The enzyme from Escherichia coli has three separate active sites, which are connected by a molecular tunnel that is almost 100 A in length [8]. The amidotransferase domain within the small subunit of the enzyme hydrolyses glutamine to ammonia via a thioester intermediate. The ammonia migrates through the interior of the protein, where it reacts with carboxy phosphate to produce the carbamate intermediate. The carboxy-phosphate intermediate is formed by the phosphorylation of bicarbonate by ATP at a site contained within the N-terminal half of the large subunit. The carbamate intermediate is transported through the interior of the protein to a second site within the C-terminal half of the large subunit, where it is phosphorylated by another ATP to yield the final product, carbamoyl phosphate [6]. carbamoyl-phosphate synthase (glutamine-hydrolysing) RL00387 branched chain ketoacid dehydrogenase kinase branched-chain amino acid catabolism 2.7.11.4 Rat 10116 9381974,7840610, Since the E1 component is rate-limiting for activity and also the component of the complex inhibited by phosphorylation, this decrease in number further limits overall enzyme activity and makes the complex more sensitive to regulation by phosphorylation in this nutritional state[9381974]#The branched-chain alpha-ketoacid dehydrogenase complex, catalyst for the rate-limiting step of branched-chain amino acid catabolism, is controlled by a highly specific protein kinase (branched-chain alpha-ketoacid dehydrogenase kinase) that associates tightly with the complex[7840610]# The enzyme has no activating compound but is specific for its substrate. It is a mitochondrial enzyme associated with the branched-chain 2-oxoacid dehydrogenase complex. Phosphorylation inactivates EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring). [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] RL00388 malate dehydrogenase the NADH shuttle that produces ATP in glucose metabolism 1.1.1.37 Mouse 10090 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glyoxylate and dicarboxylate metabolism:map00630#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Energy Metabolism:Carbon fixation:map00710# 6088170, The activity of triokinase also increased on the sucrose diet in the 3 rodent species, suggesting a coordinative substrate effect on the induction of these two rate-limiting fructolysis enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)FAU - Shafrir, E[6088170]# Also oxidizes some other 2-hydroxydicarboxylic acids. malate dehydrogenase RL00389 glycerol kinase glycerol metabolism 2.7.1.30 E.coli 83333 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 11811537, The reason is low activity of glycerol kinase (GK), the rate-limiting enzyme in glycerol metabolism[11811537]# Glycerone and L-glyceraldehyde can act as acceptors; UTP (and, in the case of the yeast enzyme, ITP and GTP) can act as donors. glycerol kinase RL00390 pyruvate kinase glycolysis 2.7.1.40 Rat 10116 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Energy Metabolism:Carbon fixation:map00710# 16046853,291050,2846196, The major rate-limiting step for glycolysis was the transport of glucose across the blood-brain barrier into the brain[16046853]#The increased glycolytic capacity is related to high levels of rate-limiting glycolytic enzymes, such as pyruvate kinase (EC 2.7.1.40)[291050]#All rate-limiting enzymes of glucose metabolism which were studied (glucose-6-phosphate dehydrogenase, total hexokinases, pyruvate kinase, fructose-1,6-bisphosphatase) revealed markedly reduced activity, only glucose-6-phosphatase activity was increased[2846196]# UTP, GTP, CTP, ITP and dATP can also act as donors. Also phosphorylates hydroxylamine and fluoride in the presence of CO2. pyruvate kinase RL00391 farnesyl diphosphate synthetase ergosterol biosynthesis in yeast 2.5.1.10 Yeast 4932 Metabolism:Biosynthesis of Secondary Metabolites:Terpenoid biosynthesis:map00900#Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 1779710, The isolation of the functional ERG20 gene allowed us to show that farnesyl diphosphate synthetase could be a rate limiting enzyme in ergosterol biosynthesis in yeast[1779710]# Some forms of this enzyme will also use dimethylallyl diphosphate as a substrate. The enzyme will not accept larger prenyl diphosphates as efficient donors. geranyltranstransferase RL00392 ceramide galactosyltransferase cerebroside synthesis 2.4.1.45 Rat 10116 9387870,9681444, With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-regulation of mRNA levels for myelin P0 protein, ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis)[9387870]#We found that, during development of the rat sciatic nerve, expression of mRNA for hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, was up-regulated in parallel with mRNA for P0, the major structural protein of PNS myelin, and with ceramide galactosyltransferase (CGT), the rate-limiting enzyme in cerebroside biosynthesis[9681444]# Highly specific. 2-hydroxyacylsphingosine 1-beta-galactosyltransferase RL00393 thymidine kinase synthesis of dTTP/the salvage pathway of nucleotide metabolism 2.7.1.21 Mouse 10090 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 9816259, 5'-AdThd is a thymidine analogue that at low concentrations (<30 micrometer) can increase thymidine kinase activity, which is the rate-limiting enzyme for activation of IdUrd[9816259]# Deoxyuridine can also act as acceptor, and dGTP can act as a donor. The deoxypyrimidine kinase complex induced by Herpes simplex virus catalyses this reaction as well as those of EC 2.7.1.114 (AMP---thymidine kinase), EC 2.7.1.118 (ADP---thymidine kinase) and EC 2.7.4.9 (dTMP-kinase). thymidine kinase RL00394 cholesterol 7alpha-hydroxylase bile acid synthesis/the synthesis of the cofactor for PAH(phenylalanine hydroxylase ) 1.14.13.17 Rat 10116 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 10656290,10744771, Preincubation of rat liver microsomes with iron (Fe)/ascorbate (50 microM/200 microM), known to induce peroxidation, resulted in a significant inhibition of (i) the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (46%, p < .01), (ii) the crucial enzyme controlling the conversion of cholesterol in bile acids, cholesterol 7alpha-hydroxylase (48%, p < .001), and (iii) the central enzyme for cholesterol esterification: Acyl-CoA:cholesterol acyltransferase (ACAT, 80%, p < .0001)[10656290]#The objective of this study was to investigate the mechanism of action of peroxisome proliferators and PPARalpha on the transcription of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver[10744771]# A heme-thiolate protein (P-450). cholesterol 7alpha-monooxygenase RL00395 carbonic anhydrase CO2 hydration 4.2.1.1 Mouse 10090 Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 9882455, The rate-limiting step in the catalysis of the hydration of CO2 by carbonic anhydrase involves transfer of protons between zinc-bound water and solution[9882455]# A zinc protein. carbonate dehydratase RL00396 glycogen synthase nonoxidative pathway/glycogen synthesis of skeletal muscle 2.4.1.11 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 10684630, As the GPI-PLC reaction is rate limiting, the efficiency of the two-step anchor cleavage was significantly increased when insulin was present together with glucose as compared to glucose alone[10684630]# The accepted name varies according to the source of the enzyme and the nature of its synthetic product (cf. EC 2.4.1.1, phosphorylase). Glycogen synthase from animal tissues is a complex of a catalytic subunit and the protein glycogenin. The enzyme requires glucosylated glycogenin as a primer; this is the reaction product of EC 2.4.1.186 (glycogenin glucosyltransferase). A similar enzyme utilizes ADP-glucose (EC 2.4.1.21, starch synthase). glycogen(starch) synthase RL00397 glycogen synthase nonoxidative pathway/glycogen synthesis of skeletal muscle 2.4.1.11 Mouse 10090 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 10067873, The enzymatic activity of glycogen synthase, the rate-limiting enzyme for glycogen synthesis, was significantly lower in livers of knockout mice than in livers from wild-type controls on embryonic day 18 and postnatal day 0[10067873]# The accepted name varies according to the source of the enzyme and the nature of its synthetic product (cf. EC 2.4.1.1, phosphorylase). Glycogen synthase from animal tissues is a complex of a catalytic subunit and the protein glycogenin. The enzyme requires glucosylated glycogenin as a primer; this is the reaction product of EC 2.4.1.186 (glycogenin glucosyltransferase). A similar enzyme utilizes ADP-glucose (EC 2.4.1.21, starch synthase). glycogen(starch) synthase RL00398 glycogen synthase nonoxidative pathway/glycogen synthesis of skeletal muscle 2.4.1.11 Yeast 4932 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 10684630, As the GPI-PLC reaction is rate limiting, the efficiency of the two-step anchor cleavage was significantly increased when insulin was present together with glucose as compared to glucose alone[10684630]# The accepted name varies according to the source of the enzyme and the nature of its synthetic product (cf. EC 2.4.1.1, phosphorylase). Glycogen synthase from animal tissues is a complex of a catalytic subunit and the protein glycogenin. The enzyme requires glucosylated glycogenin as a primer; this is the reaction product of EC 2.4.1.186 (glycogenin glucosyltransferase). A similar enzyme utilizes ADP-glucose (EC 2.4.1.21, starch synthase). glycogen(starch) synthase RL00399 tryptophan 2,3-dioxygenase kynurenine pathway/tryptophan catabolism 1.13.11.11 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 10966936, Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels[10966936]# A protohemoprotein. In mammals, the enzyme appears to be located only in the liver. This enzyme, together with EC 1.13.11.52, indoleamine 2,3-dioxygenase, catalyses the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism [5]. The enzyme is specific for tryptophan as substrate, but is far more active with L-tryptophan than with D-tryptophan [2]. tryptophan 2,3-dioxygenase RL00401 phenylalanine hydroxylase hepatic phenylalanine metabolism 1.14.16.1 Rat 10116 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400# 16429477, This study investigated the relationship between the parameters of PheBT, performed with air isotope ratio mass spectrometry, and the activity of phenylalanine hydroxylase (PAH), the phenylalanine metabolism rate-limiting enzyme, in rat liver, and proposes valid parameters for the assessment of liver function[16429477]# The active centre contains mononuclear iron(II). The reaction involves an arene oxide that rearranges to give the phenolic hydroxy group. This results in the hydrogen at C-4 migrating to C-3 and in part being retained. This process is known as the NIH-shift. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34, 6,7-dihydropteridine reductase, or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. phenylalanine 4-monooxygenase RL00402 phenylalanine hydroxylase hepatic phenylalanine metabolism 1.14.16.1 Mouse 10090 Metabolism:Amino Acid Metabolism:Phenylalanine, tyrosine and tryptophan biosynthesis:map00400# 10984661, The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the rate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofactor of three aromatic amino acid hydroxylases, one of which is phenylalanine hydroxylase[10984661]# The active centre contains mononuclear iron(II). The reaction involves an arene oxide that rearranges to give the phenolic hydroxy group. This results in the hydrogen at C-4 migrating to C-3 and in part being retained. This process is known as the NIH-shift. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34, 6,7-dihydropteridine reductase, or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. phenylalanine 4-monooxygenase RL00403 phosphatidate phosphohydrolase triacylglycerol(TG) synthesis/the de novo synthesis of lipids and cholesterol 3.1.3.4 Mouse 10090 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600#Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Ether lipid metabolism:map00565#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 7407220, In all cellular preparations studied, the ratio of neutral lipid (diacylglycerol + triacylglycerol) to total lipid (phosphatic acid + neutral lipid) was low, suggesting that phosphatidate phosphohydrolase may be rate limiting in intestinal neutral glycerolipid biosynthesis.[7407220]# phosphatidate phosphatase RL00404 Indoleamine 2,3-dioxygenase the kynurenine pathway of tryptophan metabolism/UV filter biosynthesis 1.13.11.52 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 17933973,1071924,16319139, Heme oxygenase-1 (HO-1) is the rate limiting enzyme of heme catabolism whereas indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan through the kynurenine pathway[16319139]# A protohemoprotein. Requires ascorbic acid and methylene blue for activity. This enzyme has broader substrate specificity than EC 1.13.11.11, tryptophan 2,3-dioxygenase [1]. It is induced in response to pathological conditions and host-defense mechanisms and its distribution in mammals is not confined to the liver [2]. While the enzyme is more active with D-tryptophan than L-tryptophan, its only known function to date is in the metabolism of L-tryptophan [2,6]. Superoxide radicals can replace O2 as oxygen donor [4,7]. indoleamine 2,3-dioxygenase RL00405 ATP-dependent citrate lyase the de novo synthesis of lipids and cholesterol 6.2.1.5 Rat 10116 Metabolism:Carbohydrate Metabolism:C5-Branched dibasic acid metabolism:map00660#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 16101500,3108130,6109001, The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase)[16101500]#These data indicate preferential localization of ATP-citrate lyase in cholinergic nerve endings, and indicate that this enzyme is not a rate limiting step in the synthesis of the acetyl moiety of ACh in brain.[6109001]#The effect of thyroparathyroidectomy (TPTX) on ATP citrate lyase regulation, a rate-limiting enzyme of fatty acid synthesis in hepatic cytosol, was investigated in rats refed after a 24 h fast[3108130]# succinate---CoA ligase (ADP-forming) RL00406 ATP-dependent citrate lyase the de novo synthesis of lipids and cholesterol 6.2.1.5 Mouse 10090 Metabolism:Carbohydrate Metabolism:C5-Branched dibasic acid metabolism:map00660#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 16101500,6109001, The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase)[16101500]#These data indicate preferential localization of ATP-citrate lyase in cholinergic nerve endings, and indicate that this enzyme is not a rate limiting step in the synthesis of the acetyl moiety of ACh in brain.[6109001]# succinate---CoA ligase (ADP-forming) RL00407 Uridine-cytidine nucleoside kinase pyrimidine-nucleotide salvage pathway 2.7.1.48 Rat 10116 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 9923963, The activity of uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48), the rate-limiting enzyme of the UMP salvage pathway, was measured in human ovaries and ovarian carcinomas, in a spectrum of six rat hepatomas of different growth rates and in eleven normal rat tissues of high and low cell renewal rates[9923963]# Cytidine can act as acceptor; GTP and ITP can act as donors. uridine kinase RL00409 xylulokinase xylose metabolism/xylose fermentation 2.7.1.17 Yeast 4932 Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040# 10981687, The xylulokinase reaction has been proposed to be the rate-limiting step in the D-xylulose fermentation with S[10981687]# xylulokinase RL00412 cysteine sulfinate decarboxylase the biosynthesis of taurine 4.1.1.29 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 10993179, In the present study, gene expression of rate-limiting enzyme for taurine biosynthesis, cysteine sulfinate decarboxylase (CSD) were examined in rat mammary gland[10993179]# A pyridoxal-phosphate protein. Also acts on L-cysteate. The 1992 edition of the Enzyme List erroneously gave the name sulfoalanine decarboxylase to this enzyme. sulfinoalanine decarboxylase RL00413 3-hydroxy-methylglutaryl coenzyme A cholesterol synthesis/the isoprenoid biosynthetic pathway 1.1.1.34 Rat 10116 Metabolism:Lipid Metabolism:Biosynthesis of steroids:map00100# 10084306,10204089, The rate-limiting enzymes of cholesterol (HMG CoA reductase) and ceramide (serine palmitoyl transferase) synthesis were not affected[10084306]#Toxicological evaluation was performed in serum samples following the administration of the therapeutic dose regimens of the compounds that were previously shown to be effective in inhibition of 3-hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase, the enzyme controlling the rate-limiting step in the synthesis of cholesterol, and acyl-CoA cholesterol acyl transferase (ACAT) which converts intracellular free cholesterol to cholesterol ester[10204089]# The enzyme is inactivated by EC 2.7.11.31 {[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase} and reactivated by EC 3.1.3.47 {[hydroxymethylglutaryl-CoA reductase (NADPH)]-phosphatase}. hydroxymethylglutaryl-CoA reductase (NADPH) RL00414 sphingosine kinase synthesis of sphingosine 1-phosphate 2.7.1.91 Rat 10116 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600#Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Environmental Information Processing:Signal Transduction:VEGF signaling pathway:map04370# 14568343, These signalling events downstream of lpR activation were inhibited to varying degrees by pertussis toxin (PTX) pretreatment or by the inhibition of sphingosine kinase (SK), a rate-limiting enzyme in the biosynthesis of S1P from sphingosine[14568343]# sphinganine kinase RL00415 sphingosine kinase synthesis of sphingosine 1-phosphate 2.7.1.91 Mouse 10090 Metabolism:Lipid Metabolism:Sphingolipid metabolism:map00600#Environmental Information Processing:Signal Transduction:Calcium signaling pathway:map04020#Environmental Information Processing:Signal Transduction:VEGF signaling pathway:map04370# 15451787, BACKGROUND: Phosphorylation of sphingosine by sphingosine kinase (SK) is the rate-limiting step in the cellular synthesis of sphingosine 1-phosphate (S1P)[15451787]# sphinganine kinase RL00416 Inosine monophosphate dehydrogenase the de novo synthesis of guanine nucleotides from IMP 1.1.1.205 Rat 10116 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983# 17100698, Mycophenolic acid (MPA) is a highly selective, non-competitive and reversible inhibitor of the inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides[17100698]# The enzyme acts on the hydroxy group of the hydrated derivative of the substrate. IMP dehydrogenase RL00417 Inosine monophosphate dehydrogenase the de novo synthesis of guanine nucleotides from IMP 1.1.1.205 Yeast 4932 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983# 11003640,12746440,11441018,15292516, IMP dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides[11003640]#IMP dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo synthesis of GTP[12746440]#IMP dehydrogenase is a rate-limiting enzyme involved in the synthesis of GTP[11441018]#IMP dehydrogenase (IMPDH) is the rate-limiting enzyme for de novo GMP synthesis[15292516]# The enzyme acts on the hydroxy group of the hydrated derivative of the substrate. IMP dehydrogenase RL00418 Thymidylate synthase the synthesis of pyrimidine nucleotides 2.1.1.45 E.coli 83333 Metabolism:Metabolism of Cofactors and Vitamins:One carbon pool by folate:map00670#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 8805515, BACKGROUND: Thymidylate synthase (TS) is critical to DNA synthesis as it catalyzes the rate limiting step in the only biosynthetic pathway for deoxythymidine monophosphate (dTMP) production[8805515]# thymidylate synthase RL00419 phosphoenolpyruvate carboxykinase (GTP) Glyceroneogenesis 4.1.1.32 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 10556529,16330542,8567635,8971075,16458327, Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis in the liver[10556529]#Here we show that the coactivator-associated arginine methyltransferase 1 (CARM1) is required for cAMP-mediated activation of rate-limiting gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and glucose-6-phosphatase genes[16330542]#Expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in hepatic gluconeogenesis, is primarily regulated at the level of gene transcription[8567635]#Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis[8971075]#Effects of endurance training on the phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme of gluconeogenesis, were studied in the obese Zucker rats[16458327]# ITP can act as phosphate donor. phosphoenolpyruvate carboxykinase (GTP) RL00421 phosphatidylinositol 4-kinase production of phosphatidylinositol 4,5-bisphosphate 2.7.1.67 Rat 10116 Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562# 8190262, As phosphatidylinositol 4-kinase is the rate-limiting enzyme for the production of phosphatidylinositol 4,5-bisphosphate, which is the preferred substrate for phospholipase C, we investigated the expression of phosphatidylinositol 4-kinase messenger RNA[8190262]# This reaction is catalysed by at least two different isoforms. 1-phosphatidylinositol 4-kinase RL00422 carbamyl phosphate synthetase I urea cycle/urea production 6.3.4.16 Mouse 10090 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 7459875, Determinations of specific activities of the other enzymes in this pathway reveal that the activity of carbamyl phosphate synthetase II, the rate-limiting step, is elevated 2- to 3-fold in both resistant lines[7459875]# carbamoyl-phosphate synthase (ammonia) RL00424 delta-aminolevulinic acid synthase heme biosynthesis 4.2.1.24 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 10634305,1959865,1526942, The activities of delta-aminolevulinic acid synthase, a rate-limiting enzyme in the heme biosynthesis, and porphobilinogen synthase in the liver of rhIL-1beta-induced fevered rat were significantly lower than those in the control, whereas the activity of heme oxygenase, a key enzyme in the heme-degradative pathway, markedly increased in the fevered rat[10634305]#These data suggest that delta-aminolevulinic acid is an inappropriate precursor for studies of the rate of heme biosynthesis, presumably because it bypasses delta-aminolevulinic acid synthase, the physiological rate-limiting enzyme in the heme biosynthetic pathway[1959865]#The major differences between the flight group and the synchronous control were elevations in microsomal protein, liver glycogen content, tyrosine aminotransferase, and tryptophan oxygenase and reductions in sphingolipids and the rate-limiting enzyme of heme biosynthesis, delta-aminolevulinic acid synthase[1526942]# The fungal enzyme is a metalloprotein. porphobilinogen synthase RL00425 Glucose-6-phosphatase gluconeogenesis 3.1.3.9 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 12507516, Expression of glucose-6-phosphatase (G6Pase), one of the rate-limiting enzymes of hepatic gluconeogenesis, has recently been shown to be transactivated by the transcription factor FKHR[12507516]# Wide distribution in animal tissues. Also catalyses potent transphosphorylations from carbamoyl phosphate, hexose phosphates, diphosphate, phosphoenolpyruvate and nucleoside di- and triphosphates, to D-glucose, D-mannose, 3-methyl-D-glucose or 2-deoxy-D-glucose [cf. EC 2.7.1.62 (phosphoramidate---hexose phosphotransferase), EC 2.7.1.79 (diphosphate---glycerol phosphotransferase) and EC 3.9.1.1 (phosphoamidase)]. glucose-6-phosphatase RL00426 tetrahydrofolate dehydrogenase metabolism of folate 1.5.1.15 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:One carbon pool by folate:map00670# 718836, The activity of tetrahydrofolate dehydrogenase, the first and rate-limiting enzyme in the metabolism of folate, was increased in the folate supplemented rats (group C) and reduced in the rats given a folic acid-free diet (group A)[718836]# methylenetetrahydrofolate dehydrogenase (NAD+) RL00427 cyclooxygenase the production of prostanoids/prostaglandin synthesis 1.14.99.1 Mouse 10090 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 16516846,16331615,16753269, Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in the synthesis of prostaglandins[16331615]#We investigated the effect of MG132 on the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of PGE(2), using macrophage cell line, Raw264.7[16516846]#Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins[16753269]# This enzyme acts both as a dioxygenase and as a peroxidase. prostaglandin-endoperoxide synthase RL00428 coproporphyrinogen oxidase heme synthesis 1.3.3.3 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 11368326, While ALAS induction is necessary for increased heme synthesis, these data indicate that other enzymes, in particular coproporphyrinogen oxidase, represent down-stream rate-limiting steps[11368326]# coproporphyrinogen oxidase RL00429 glucose-6-phosphate dehydrogenase pentose phosphate pathway (PPP)/the GSH- and NADPH-dependent H(2)O(2) elimination by PC12 cells/NADPH production 1.1.1.49 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030# 16849632,12829617,14757696, Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction[16849632]#Glucose-6-phosphate dehydrogenase (G6PD) functions as the first and rate-limiting enzyme in the pentose phosphate pathway, responsible for the generation of NADPH in a reaction coupled to the de novo production of cellular ribose[12829617]#Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, generates NADPH in a reaction linked to the de novo production of ribose[14757696]# Also acts slowly on beta-D-glucose and other sugars. Certain preparations reduce NAD+ as well as NADP+. glucose-6-phosphate dehydrogenase RL00430 gamma glutamyl transferase glutathione synthesis 2.3.2.2 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Metabolism of Other Amino Acids:Cyanoamino acid metabolism:map00460#Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 12780970, Although aspects of the glutathione antioxidant repertoire were similarly diminished with high-intensity xanthine oxidase stress, low-dose (long duration) xanthine oxidase stress augmented the activities of type II cell glutathione peroxidase and gamma-glutamyl transferase (the rate-limiting enzyme in glutathione synthesis)[12780970]# gamma-glutamyltransferase RL00431 gamma glutamyl transferase glutathione synthesis 2.3.2.2 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Metabolism of Other Amino Acids:Cyanoamino acid metabolism:map00460#Metabolism:Metabolism of Other Amino Acids:Selenoamino acid metabolism:map00450#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 12780970,15006645, Although aspects of the glutathione antioxidant repertoire were similarly diminished with high-intensity xanthine oxidase stress, low-dose (long duration) xanthine oxidase stress augmented the activities of type II cell glutathione peroxidase and gamma-glutamyl transferase (the rate-limiting enzyme in glutathione synthesis)[12780970]#The increase in activity of both GPX and GST corresponded with increased transcription of these enzymes, as well as the rate-limiting enzyme in GSH synthesis, gamma-glutamyl transferase[15006645]# gamma-glutamyltransferase RL00432 sn glycerol phosphate acyl transferase 2.3.1.15 Rat 10116 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 2303421,813635,12464581, Glycerol-3-phosphate acyltransferase (GPAT) represents the first committed step and probably the rate limiting step in glycerolipid synthesis and thus may be a good candidate for study[2303421]#It is concluded that, at optimum substrate concentrations, the activity of glycerol phosphate acyltransferase is rate-limiting in the synthesis of phosphatidate by rat liver microsomal fractions[813635]#When activated, AMPK increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3-phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis[12464581]# Acyl-[acyl-carrier protein] can also act as acyl donor. The enzyme acts only on derivatives of fatty acids of chain length above C10 glycerol-3-phosphate O-acyltransferase RL00433 sn glycerol phosphate acyl transferase 2.3.1.15 Mouse 10090 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 12730219,14724270, Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays an important role in dietary fat absorption by catalyzing a rate-limiting step in the re-synthesis of diacylglycerols in enterocytes[12730219]#Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and rate-limiting step of glycerolipid synthesis[14724270]# Acyl-[acyl-carrier protein] can also act as acyl donor. The enzyme acts only on derivatives of fatty acids of chain length above C10 glycerol-3-phosphate O-acyltransferase RL00435 beta1 n acetylglucosaminyltransferase synthesis of selectin ligands 2.4.1.143 Mouse 10090 Metabolism:Glycan Biosynthesis and Metabolism:N-Glycan biosynthesis:map00510#Metabolism:Glycan Biosynthesis and Metabolism:Glycan structures - Biosynthesis 1:map01030# 11250723, Associations linking the importance of glycosylation events to tumor biology, especially the progression to metastatic disease, have been noted over many years, Recently, a mouse model in which beta1,6-N-acetylglucosaminyltransferase V (a rate-limiting enzyme in the N-glycan pathway) has been knocked out, was used to demonstrate the importance of glycosylation in tumor progression[11250723]# R represents the remainder of the N-linked oligosaccharide in the glycoprotein acceptor. Note that this enzyme acts after N-acetylglucosaminyltransferase I but before N-acetylglucosaminyltransferases III, IV, V and VI (click here for diagram). alpha-1,6-mannosyl-glycoprotein RL00436 5-aminolevulinate synthase hepatic heme biosynthesis 2.3.1.37 Mouse 10090 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 12393745, The erythroid-specific isoform of 5-aminolevulinate synthase (ALAS2) catalyzes the rate-limiting step in heme biosynthesis[12393745]# A pyridoxal-phosphate protein. The enzyme in erythrocytes is genetically distinct from that in other tissues. 5-aminolevulinate synthase RL00437 medium chain acyl coA dehydrogenase medium-chain fatty acid beta-oxidation 1.3.99.2 Rat 10116 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 8941110, In contrast, the activity and steady-state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or post-translational levels in the hypertrophied but nonfailing ventricle[8941110]# A flavoprotein; forms, with another flavoprotein ('electron-transferring flavoproteins') and EC 1.5.5.1 electron-transferring-flavoprotein dehydrogenase, a system reducing ubiquinone and other acceptors. butyryl-CoA dehydrogenase RL00438 medium chain acyl coA dehydrogenase medium-chain fatty acid beta-oxidation 1.3.99.2 Mouse 10090 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 9177236, Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level[9177236]# A flavoprotein; forms, with another flavoprotein ('electron-transferring flavoproteins') and EC 1.5.5.1 electron-transferring-flavoprotein dehydrogenase, a system reducing ubiquinone and other acceptors. butyryl-CoA dehydrogenase RL00439 dihydropyrimidine dehydrogenase 5-fluorouracil (5-FU) chemotherapy catabolic pathway 1.3.1.2 Rat 10116 Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 10348793, In the present study, the influence of liver damage induced by bile duct ligation on dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism, CYP2B, and 5-FU pharmacokinetics were compared in male Sprague-Dawley rats[10348793]# Also acts on dihydrothymine. dihydropyrimidine dehydrogenase (NADP+) RL00440 N-acetyltransferase melatonin synthesis 2.3.1.5 Rat 10116 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232#Metabolism:Xenobiotics Biodegradation and Metabolism:Trinitrotoluene degradation:map00633# 10471401,10721063,10467435, In our previous studies, the opioid receptors located on pinealocytes have been identified and characterized, and these receptors have been found to play a stimulatory role in melatonin synthesis by activating the rate limiting enzyme, N-acetyltransferase (NAT)[10471401]#Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocarcinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth[10721063]#Caffeine, an important member of methylxanthines, induced a prolonged nocturnal rise in pineal melatonin content and an increase in its rate-limiting enzyme serotonin N-acetyltransferase (NAT) activity[10467435]# Wide specificity for aromatic amines, including serotonin; also catalyses acetyl-transfer between arylamines without CoA. arylamine N-acetyltransferase RL00441 ornithine delta aminotransferase synthesis of transmitter glutamate and gamma-aminobutyric acid ( GABA ) 2.6.1.13 Mouse 10090 Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330# 11691635, The specific activity of only ornithine aminotransferase (OAT), the rate-limiting enzyme in the conversion of ornithine to proline, increased in 2 weeks of hypertrophy[11691635]# A pyridoxal-phosphate protein. ornithine aminotransferase RL00442 phosphofructokinase glycolysis 2.7.1.11 Rat 10116 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 16103521, Microarrays and RNAse protection assays were used to assess the expression of several electron transport chain components (cytochrome-c oxidase subunits Cox 5A, Cox 5B, and Cox 6A, ATP synthase, and ATP synthase subunit 5B) and of the rate-limiting enzyme for glycolysis, phosphofructokinase (PFK)[16103521]# D-Tagatose 6-phosphate and sedoheptulose 7-phosphate can act as acceptors. UTP, CTP and ITP can act as donors. Not identical with EC 2.7.1.105 6-phosphofructo-2-kinase. 6-phosphofructokinase RL00443 phosphofructokinase glycolysis 2.7.1.11 E.coli 83333 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 1100623, Alterations in the level of ATP apparently affect the velocity of phosphofructokinase, the rate-limiting enzyme in glycolsis, altering the cellular levels of glucose-6-P or fructose-P2[1100623]# D-Tagatose 6-phosphate and sedoheptulose 7-phosphate can act as acceptors. UTP, CTP and ITP can act as donors. Not identical with EC 2.7.1.105 6-phosphofructo-2-kinase. 6-phosphofructokinase RL00446 7alpha-hydroxylase bile acid synthesis/the synthesis of the cofactor for PAH(phenylalanine hydroxylase ) 1.14.13.17 Mouse 10090 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 17908794,17237956, Intriguingly, while the expression of Cyp8b1 is almost extinguished in the livers of mice that lack LRH-1, the expression of the rate-limiting enzyme of BA synthesis, i.e., Cyp7a1, remains unchanged[17908794]#This study aimed to evaluate the expression pattern within the liver architecture of the rate-limiting enzyme of the neutral pathway, cholesterol 7alpha-hydroxylase (Cyp7a1), and sterol 12alpha-hydroxylase (Cyp8b1), the enzyme necessary for the synthesis of cholic acid[17237956]# A heme-thiolate protein (P-450). cholesterol 7alpha-monooxygenase RL00447 diacylglycerol acyltransferase diacylglycerol conversion to triacylglycerol 2.3.1.20 Rat 10116 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830# 2737209,2559137, The rate-limiting role of diacylglycerol acyltransferase[2737209]#Rat liver acyl coenzyme A:diacylglycerol acyltransferase, an intrinsic membrane activity associated with the endoplasmic reticulum, catalyzes the terminal and rate-limiting step in triglyceride synthesis[2559137]# Palmitoyl-CoA and other long-chain acyl-CoAs can act as donors. diacylglycerol O-acyltransferase RL00448 cyclooxygenase the production of prostanoids/prostaglandin synthesis 1.14.99.1 Rat 10116 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 10365086,10024686, There was no significant difference in cyclooxygenase (COX) activity and COX-2 mRNA level between BRF and NRF, indicating that the change in PGE2 production was independent of COX, a rate-limiting enzyme for the production of PGE2[10365086]#One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX)[10024686]# This enzyme acts both as a dioxygenase and as a peroxidase. prostaglandin-endoperoxide synthase RL00449 dipeptidyl peptidase the hydrolysis of the alanine substrates 3.4.14.5 Rat 10116 12223360, Moreover, as estimated from the residual peptide structure and confirmed by exogenous peptidase supplementation, dipeptidyl peptidase IV and dipeptidyl carboxypeptidase I were identified as the rate-limiting enzymes in the digestive breakdown of these peptides[12223360]# A homodimer. An integral protein of the plasma membrane of lymphocytes and other mammalian cells, in peptidase family S9 (prolyl oligopeptidase family). The reaction is similar to that of the unrelated EC 3.4.14.11 Xaa-Pro dipeptidyl-peptidase of lactococci dipeptidyl-peptidase IV RL00450 branched-chain alpha-keto acid dehydrogenase complex the branched-chain amino acid catabolism 1.8.1.4 Rat 10116 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 16616211,15173434,11641455,10885793, The mechanism responsible for this phenomenon is attributed to activation of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the second-step reaction of the BCAA catabolic pathway and is the rate-limiting enzyme in the pathway[15173434]#Clofibric acid (an active metabolite of clofibrate) is known to promote the BCAA catabolism by activation of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), the rate-limiting enzyme of the BCAA catabolism[16616211]#The rate-limiting step of branched-chain amino acid oxidation is performed by the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKAD), which is regulated by a deactivating kinase[11641455]#Feeding the BCAA diet increased serum BCAA concentrations and activity of the hepatic branched-chain alpha-keto acid dehydrogenase complex, the rate-limiting enzyme in the catabolism of BCAA, suggesting that dietary BCAA promotes BCAA catabolism[10885793]# A flavoprotein (FAD). A component of the multienzyme 2-oxo-acid dehydrogenase complexes. In the pyruvate dehydrogenase complex, it binds to the core of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, and catalyses oxidation of its dihydrolipoyl groups. It plays a similar role in the oxoglutarate and 3-methyl-2-oxobutanoate dehydrogenase complexes. Another substrate is the dihydrolipoyl group in the H-protein of the glycine-cleavage system (click here for diagram), in which it acts, together with EC 1.4.4.2, glycine dehydrogenase (decarboxylating), and EC 2.1.2.10, aminomethyltransferase, to break down glycine. It can also use free dihydrolipoate, dihydrolipoamide or dihydrolipoyllysine as substrate. This enzyme was first shown to catalyse the oxidation of NADH by methylene blue; this activity was called diaphorase. The glycine cleavage system is composed of four components that only loosely associate: the P protein (EC 1.4.4.2), the T protein (EC 2.1.2.10), the L protein (EC 1.8.1.4) and the lipoyl-bearing H protein [6]. dihydrolipoyl dehydrogenase RL00451 branched-chain alpha-keto acid dehydrogenase complex the branched-chain amino acid catabolism 1.8.1.4 Mouse 10090 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 16875466, The BCKDH (branched-chain alpha-keto acid dehydrogenase complex) catalyses the rate-limiting step in the oxidation of BCAAs (branched-chain amino acids)[16875466]# A flavoprotein (FAD). A component of the multienzyme 2-oxo-acid dehydrogenase complexes. In the pyruvate dehydrogenase complex, it binds to the core of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, and catalyses oxidation of its dihydrolipoyl groups. It plays a similar role in the oxoglutarate and 3-methyl-2-oxobutanoate dehydrogenase complexes. Another substrate is the dihydrolipoyl group in the H-protein of the glycine-cleavage system (click here for diagram), in which it acts, together with EC 1.4.4.2, glycine dehydrogenase (decarboxylating), and EC 2.1.2.10, aminomethyltransferase, to break down glycine. It can also use free dihydrolipoate, dihydrolipoamide or dihydrolipoyllysine as substrate. This enzyme was first shown to catalyse the oxidation of NADH by methylene blue; this activity was called diaphorase. The glycine cleavage system is composed of four components that only loosely associate: the P protein (EC 1.4.4.2), the T protein (EC 2.1.2.10), the L protein (EC 1.8.1.4) and the lipoyl-bearing H protein [6]. dihydrolipoyl dehydrogenase RL00452 branched-chain alpha-keto acid dehydrogenase complex the branched-chain amino acid catabolism 1.8.1.4 E.coli 83333 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 3516150, We have now determined that if the reactions catalyzed by E3 are made rate-limiting, the excess E3 functions equivalently to that in the native complex.[3516150]# A flavoprotein (FAD). A component of the multienzyme 2-oxo-acid dehydrogenase complexes. In the pyruvate dehydrogenase complex, it binds to the core of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, and catalyses oxidation of its dihydrolipoyl groups. It plays a similar role in the oxoglutarate and 3-methyl-2-oxobutanoate dehydrogenase complexes. Another substrate is the dihydrolipoyl group in the H-protein of the glycine-cleavage system (click here for diagram), in which it acts, together with EC 1.4.4.2, glycine dehydrogenase (decarboxylating), and EC 2.1.2.10, aminomethyltransferase, to break down glycine. It can also use free dihydrolipoate, dihydrolipoamide or dihydrolipoyllysine as substrate. This enzyme was first shown to catalyse the oxidation of NADH by methylene blue; this activity was called diaphorase. The glycine cleavage system is composed of four components that only loosely associate: the P protein (EC 1.4.4.2), the T protein (EC 2.1.2.10), the L protein (EC 1.8.1.4) and the lipoyl-bearing H protein [6]. dihydrolipoyl dehydrogenase RL00453 arachidonyl coA synthetase esterification of arachidonic acid by many human cells 6.2.1.3 Rat 10116 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 1769731, These data indicate that the HETEs and other 20 carbon fatty acid substrates probably compete for activity of a specific arachidonyl-CoA synthetase, which is the first and rate-limiting step for esterification of arachidonic acid by many human cells[1769731]# Acts on a wide range of long-chain saturated and unsaturated fatty acids, but the enzymes from different tissues show some variation in specificity. The liver enzyme acts on acids from C6 to C20; that from brain shows high activity up to C24. long-chain-fatty-acid---CoA ligase RL00454 glutamine-fructose-6-phosphate amidotransferase hexosamine synthesis 2.6.1.16 Mouse 10090 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251# 15613679, We have previously shown that overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine-fructose-6-phosphate amidotransferase) in adipose tissue of transgenic mice results in skeletal muscle insulin resistance and altered regulation of leptin and adiponectin[15613679]# Although the overall reaction is that of a transferase, the mechanism involves the formation of ketimine between fructose 6-phosphate and a 6-amino group from a lysine residue at the active site, which is subsequently displaced by ammonia (transamidination). glutamine---fructose-6-phosphate transaminase (isomerizing) RL00455 tyrosine hydroxylase the catecholamine biosynthetic pathway 1.14.16.2 Mouse 10090 Human Diseases:Neurodegenerative Diseases:Parkinson's disease:map05020#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 17920205,17507557,17853069,17105912,17896792,17823250,18314273,16105653,17457889,16515541,16278103,16356647,17350071,17222430,17054915,16137646,16981894,17482290,18419768,16135092, In particular, we focused on the rate-limiting catecholamine-synthesizing enzyme tyrosine hydroxylase (TH)[17105912]#Tyrosine 3-monooxygenase (tyrosine hydroxylase, TH) catalyzes the initial and rate-limiting step in the catecholamine biosynthesis[16105653]#Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of catecholamines[16515541]#Choline uptake by the high affinity choline transporter (CHT) is the rate-limiting step in acetylcholine synthesis[16278103]#To investigate the possibility that these two factors are functionally interrelated, we investigated the potential role of the androgen receptor (AR) on transcriptional activity of the tyrosine hydroxylase (TH) gene that encodes the rate-limiting enzyme of the dopamine biosynthesis pathway[16356647]#Tyrosine hydroxylase (tyrosine 3-monooxygenase, EC 1.14.16.2, TH) is the rate-limiting enzyme in the biosynthesis of catecholamine neurotransmitters, dopamine (DA), noradrenaline (NE), and adrenaline, in the neurons[17054915]#Among the most significantly up-regulated genes in DGKepsilon (+/+) mice included those encoding the inducible prostaglandin synthase cyclooxygenase-2 (COX-2) and tyrosine hydroxylase (TH), also known as tyrosine 3-monooxygenase, the rate-limiting enzyme of catecholamine biosynthesis[16137646]#TH, the rate-limiting enzyme in dopamine synthesis, converts tyrosine to l-dihydroxyphenylalanine (L-DOPA), which is then converted to dopamine by the enzyme, aromatic amino acid decarboxylase (AADC)[16981894]#One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis[16135092]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by EC 2.7.11.27, [acetyl-CoA carboxylase] kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tyrosine 3-monooxygenase RL00456 acetyl coA acetyltransferase 2.3.1.9 Rat 10116 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Lipid Metabolism:Synthesis and degradation of ketone bodies:map00072#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Xenobiotics Biodegradation and Metabolism:Benzoate degradation via CoA ligation:map00632#Environmental Information Processing:Signal Transduction:Two-component system:map02020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 2869784, The influence of clofibrate and di(2-ethylhexyl)phthalate on mitochondrial acetyl-CoA acetyltransferase (acetyl-CoA: acetyl-CoA C-acetyltransferase, EC 2.3.1.9), the rate-limiting ketogenic enzyme, which can be modified and inactivated by CoA, was investigated[2869784]# acetyl-CoA C-acetyltransferase RL00457 aminopeptidase a angiotensin degradation 3.4.11.7 Mouse 10090 Cellular Processes:Endocrine System:Renin - angiotensin system:map04614# 12765341, Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation[12765341]# Ca2+-activated and generally membrane-bound. A zinc-metallopeptidase in family M1 (membrane alanyl aminopeptidase family) glutamyl aminopeptidase RL00458 histidine ammonia lyase L-histidine degradation 4.3.1.3 Rat 10116 Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340#Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 8133, These findings demonstrate that histidine ammonia-lyase is the rate-limiting factor in L-histidine degradation in the rat[8133]# This enzyme is a member of the aromatic amino acid lyase family, other members of which are EC 4.3.1.23 (tyrosine ammonia-lyase), EC 4.3.1.24 (phenylalanine ammonia-lyase) and EC 4.3.1.25 (phenylalanine/tyrosine ammonia-lyase). The enzyme contains the cofactor 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO), which is common to this family [4]. This unique cofactor is formed autocatalytically by cyclization and dehydration of the three amino-acid residues alanine, serine and glycine [5]. This enzyme catalyses the first step in the degradation of histidine and the product, urocanic acid, is further metabolized to glutamate [2,3]. histidine ammonia-lyase RL00459 Tryptophan hydroxylase the biosynthesis of serotonin (5-HT)/ melatonin biosynthesis 1.14.16.4 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 1059145, Tryptophan hydroxylase [EC 1.14.16.4; L-tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating)], the enzyme catalyzing the rate-limiting step in the biosynthesis of serotonin, was purified 79-fold from the region of the raphe nucleus of rat midbrain by sequential column chromatography and disc-gel electrophoresis[1059145]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by a Ca2+-activated protein kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tryptophan 5-monooxygenase RL00460 aconitase 4.2.1.3 Rat 10116 Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glyoxylate and dicarboxylate metabolism:map00630#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 7589784, Mitochondria (m-)aconitase is a rate-limiting regulatory enzyme in prostate epithelial cells which minimizes citrate oxidation by these cells[7589784]# Besides interconverting citrate and cis-aconitate, it also interconverts cis-aconitate with isocitrate and, hence, interconverts citrate and isocitrate. The equilibrium mixture is 91% citrate, 6% isocitrate and 3% aconitate. cis-Aconitate is used to designate the isomer (Z)-prop-1-ene-1,2,3-tricarboxylate. An iron-sulfur protein, containing a [4Fe-4S] cluster to which the substrate binds. aconitate hydratase RL00461 hydroxysteroid transferase testosterone production 2.8.2.2 Rat 10116 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Energy Metabolism:Sulfur metabolism:map00920# 7900959, Reproductive toxicity: degenerative changes in the seminiferous epithelium, induction of the rate-limiting enzyme in testosterone production (3beta-hydroxysteroid transferase and 17 beta-hydroxysteroid transferase), histological changes in reproductive organs, testicular atrophy and the occurrence of ovarian cysts were noticed in rat[7900959]# Primary and secondary alcohols, including aliphatic alcohols, ascorbic acid, chloramphenicol, ephedrine and hydroxysteroids, but not phenolic steroids, can act as acceptors (cf. EC 2.8.2.15 steroid sulfotransferase). alcohol sulfotransferase RL00462 glutamate decarboxylase gama-amino butrylic acid (GABA) production 4.1.1.15 Mouse 10090 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Human Diseases:Metabolic Disorders:Type I diabetes mellitus:map04940#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 3725189,7038682,10407195, Neuronal structures in the barrel region of the mouse primary somatosensory cortex containing gamma-aminobutyric acid (GABA) were identified by an immunocytochemical method, using an antiserum to glutamic acid decarboxylase (GAD), the rate-limiting enzyme in the synthesis of GABA[3725189]#Two polyclonal antibodies were applied in succession, one directed against the midregion and COOH terminus of the 22-amino acid polypeptide motilin and the other against glutamic acid decarboxylase (glutamate decarboxylase; L-glutamate 1-carboxy-lyase, EC 4.1.1.15), the rate-limiting enzyme in the synthesis of the neurotransmitter GABA[7038682]#To test the hypothesis that altered GABA synthesis within nucleus reticularis thalami (NRT) neurons regulates absence seizures, we analyzed and quantitated the distribution of GAD(67) and GAD(65), the rate-limiting enzymes of GABA synthesis, in thalamic nuclei from the Cacnb4lh model of absence seizures and non-epileptic (+/+) controls[10407195]# A pyridoxal-phosphate protein. The brain enzyme also acts on L-cysteate, 3-sulfino-L-alanine and L-aspartate. glutamate decarboxylase RL00463 acyl coA : monoacylglycerol acyltransferase re-synthesis of diacylglycerols in enterocytes 2.3.1.22 Mouse 10090 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561# 12730219, Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays an important role in dietary fat absorption by catalyzing a rate-limiting step in the re-synthesis of diacylglycerols in enterocytes[12730219]# Various 2-acylglycerols can act as acceptor; palmitoyl-CoA and other long-chain acyl-CoAs can act as donors. The sn-1 position and the sn-3 position are both acylated, at about the same rate. 2-acylglycerol O-acyltransferase RL00464 D-glucosaminyl 3-O-sulfotransferase-1 2.8.2.23 Mouse 10090 Metabolism:Glycan Biosynthesis and Metabolism:Glycan structures - Biosynthesis 1:map01030#Metabolism:Glycan Biosynthesis and Metabolism:Heparan sulfate biosynthesis:map00534# 12671048, Endothelial cell production of anticoagulant heparan sulfate (HS(act)) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1)[12671048]# This enzyme differs from the other [heparan sulfate]-glucosamine 3-sulfotransferases [EC 2.8.2.29 ([heparan sulfate]-glucosamine 3-sulfotransferase 2) and EC 2.8.2.30 ([heparan sulfate]-glucosamine 3-sulfotransferase 3)] by being the most selective for a precursor of the antithrombin-binding site. It has a minimal acceptor sequence of: -> GlcNAc6S-> GlcA-> GlcN2S*+/-6S-> IdoA2S-> GlcN2S-> , the asterisk marking the target (symbols as in 2-Carb-38) using +/- to mean the presence or absence of a substituent, and > to separate a predominant structure from a minor one. Thus Glc(N2S > NAc) means a residue of glucosamine where the N carries a sulfo group mainly but occasionally an acetyl group.) [1-4]. It can also modify other precursor sequences within heparan sulfate but this action does not create functional antithrombin-binding sites. These precursors are variants of the consensus sequence: -> Glc(N2S > NAc)+/-6S-> GlcA-> GlcN2S*+/-6S-> GlcA > IdoA+/-2S-> Glc(N2S/NAc)+/-6S-> [5]. If the heparan sulfate substrate lacks 2-O-sulfation of GlcA residues, then enzyme specificity is expanded to modify selected glucosamine residues preceded by IdoA as well as GlcA [6]. [heparan sulfate]-glucosamine 3-sulfotransferase 1 RL00466 ribonucleotide reductase deoxyribonucleotide synthesis 1.17.4.1 Yeast 4932 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Cellular Processes:Cell Growth and Death:p53 signaling pathway:map04115#Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 10593972,16399800,16489218, Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides; this step is rate-limiting in DNA precursor synthesis[10593972]#Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis and is essential in DNA replication and repair[16489218]#Ribonucleotide reductase (RNR), comprising two large (R1) and two small (R2) subunits, catalyzes a rate-limiting step in the production of deoxyribonucleotides needed for DNA replication and repair[16399800]# This enzyme is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. An iron protein. While the enzyme is activated by ATP, it is inhibited by dATP [3,6]. ribonucleoside-diphosphate reductase RL00467 tissue type plasminogen activator the fibrinolytic cascade 3.4.21.68 Rat 10116 Cellular Processes:Immune System:Complement and coagulation cascades:map04610# 9610055, We investigated whether tissue plasminogen activator (tPA), a plasma serine protease that catalyzes the initial and rate-limiting step in fibrinolysis, inhibits postoperative intraperitoneal adhesion formation in rats[9610055]# A peptidase of family S1 (trypsin family) from a wide variety of mammalian tissues, especially endothelial cells. Secreted as a single chain precursor which is cleaved to a two-chain form by plasmin. Activity is considerably enhanced by fibrin. Formerly included in EC 3.4.21.31 and EC 3.4.99.26 t-plasminogen activator RL00468 ornithine decarboxylase polyamine metabolism 4.1.1.17 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 11853879,9191978,14607835,9884080,7865470,9224728,15228220,8912847,12856719,7874572,18381427,12860970,11782361, Ornithine decarboxylase (ODC) is the rate-limiting enzyme in the biosynthesis of polyamines, a family of cationic compounds required for optimal cell proliferation and differentiation[11853879]#We also found that the basal activity of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, was higher in Wobbler mice than in control animals[9191978]#Our results identify mammalian eIF4E as rate-limiting for cell cycle progression before it regulates cell growth[14607835]#We have examined the role in B cell activation of ornithine decarboxylase (ODC), the labile rate-limiting enzyme in the synthesis of polyamines thought to be required for S phase entry in all cells[7865470]#We have examined whether modulation of the polyamine biosynthetic pathway, through inhibition by alpha-difluoromethylornithine (DFMO) of the rate limiting enzyme, ornithine decarboxylase (ODC), modulates NO synthesis in J774 macrophages[9884080]#The effects of 1alpha,25-(OH)2D3 were preceded by the suppression of ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine metabolism[9224728]#Increased levels or overexpression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis pathway, is characteristic of tumor cells[15228220]#pMV7-4E cells (4E-P2), which overexpress translation initiation factor eIF-4E, contain elevated levels of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine biosynthesis[8912847]#Activity of ornithine decarboxylase (ODC), one of the rate-limiting enzymes in the pathway of polyamine biosynthesis, is regulated by various factors[7874572]#We have recently shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis reduces pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice[12856719]#The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli[12860970]#We used transgenic mice to examine the effects of constitutive expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on histone acetylation in epithelial cells in skin[11782361]# A pyridoxal-phosphate protein. ornithine decarboxylase RL00469 beta hydroxysteroid dehydrogenase/isomerase sex steroid production from pregnenolone 1.1.1.145/5.3.3.1 Rat 10116 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 9065457,7018303, The rate-limiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane[9065457]#Therefore, we would propose that the major effect of chronic ethanol ingestion upon the enzymes required for testosterogenesis is the reduction of 3 beta-hydroxysteroid dehydrogenase/isomerase activity, the rate limiting step in sex steroid production from pregnenolone.[7018303]# May be at least three distinct enzymes. steroid Delta-isomerase RL00470 beta hydroxysteroid dehydrogenase/isomerase sex steroid production from pregnenolone 1.1.1.145/5.3.3.1 Mouse 10090 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Lipid Metabolism:C21-Steroid hormone metabolism:map00140# 9065457, The rate-limiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane[9065457]# May be at least three distinct enzymes. steroid Delta-isomerase RL00471 P5CS1 biosynthesis of proline 1.5.1.12 Yeast 4932 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330# 14602584, These results indicate that both enzymes, not Delta(1)-pyrroline-5-carboxylate reductase, are rate-limiting enzymes in yeast cells[14602584]# This enzyme can oxidize a number of 1-pyrrolines, e.g. 3-hydroxy-1-pyrroline-5-carboxylate is converted into 4-hydroxyglutamate and (R)-1-pyrroline-5-carboxylate is converted into D-glutamate. While NAD+ appears to be the better electron acceptor, NADP+ can also act, but more slowly [1,3]. In many organisms, ranging from bacteria to mammals, proline is oxidized to glutamate in a two-step process involving this enzyme and EC 1.5.99.8, proline dehydrogenase [3]. In many bacterial species, both activities are carried out by a single bifunctional enzyme [3,4]. 1-pyrroline-5-carboxylate dehydrogenase RL00472 amine oxidase beta-alanine and pantothenic acid biosynthesis 1.5.3.11 Yeast 4932 11154694, Using a functional screen in the yeast Saccharomyces cerevisiae, a putative amine oxidase, encoded by FMS1, was found to be rate-limiting for beta-alanine and pantothenic acid biosynthesis[11154694]# A flavoprotein requiring Fe2+. Also acts on N1-acetylspermidine and N1,N12-diacetylspermine. polyamine oxidase RL00473 adenine phosphoribosyl transferase AMP formation and subsequently the formation of ADP and ATP 2.4.2.7 Rat 10116 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 6327016, The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# 5-Amino-4-imidazolecarboxamide can replace adenine. adenine phosphoribosyltransferase RL00474 adenine phosphoribosyl transferase AMP formation and subsequently the formation of ADP and ATP 2.4.2.7 Mouse 10090 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 6327016, The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM)[6327016]# 5-Amino-4-imidazolecarboxamide can replace adenine. adenine phosphoribosyltransferase RL00475 Renin renin-angiotensin system 3.4.23.15 Rat 10116 Cellular Processes:Endocrine System:Renin - angiotensin system:map04614# 10766031, Renin is the rate-limiting step in angiotensin II production[10766031]# Formed from prorenin in plasma and kidney. In peptidase family A1 (pepsin A family). renin RL00476 Renin renin-angiotensin system 3.4.23.15 Mouse 10090 Cellular Processes:Endocrine System:Renin - angiotensin system:map04614# 10868475,15082450, Renin, as the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II, has been studied for more than 100 years[10868475]#Renin release from juxtaglomerular granular cells is considered the rate-limiting step in activation of the renin-angiotensin system that helps to maintain body salt and water balance[15082450]# Formed from prorenin in plasma and kidney. In peptidase family A1 (pepsin A family). renin RL00478 tyrosine hydroxylase the catecholamine biosynthetic pathway 1.14.16.2 Rat 10116 Human Diseases:Neurodegenerative Diseases:Parkinson's disease:map05020#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 10476677, We have employed buoyant density fractionation to separate the dopaminergic neurons of the two compartments and compare their subsequent phenotype development with respect to their expression of the gene encoding tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine biosynthetic pathway[10476677]# The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by EC 2.7.11.27, [acetyl-CoA carboxylase] kinase. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC 1.5.1.34 (6,7-dihydropteridine reductase), or slowly rearranges into the more stable compound 7,8-dihydrobiopterin. tyrosine 3-monooxygenase RL00479 hexokinase glycolysis 2.7.1.1 Rat 10116 Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 16046853,12660493,17803972,9755073,18308470, The major rate-limiting step for glycolysis was the transport of glucose across the blood-brain barrier into the brain[16046853]#The first rate-limiting enzymes in intracellular glucose metabolism are the hexokinases, which catalyze the phosphorylation of glucose[12660493]#In conclusion, the insulin-induced changes in the tracer-to-tracee ratio are due to a shift of the rate-limiting step for glucose uptake from transport to phosphorylation by hexokinase[9755073]# D-Glucose, D-mannose, D-fructose, sorbitol and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. hexokinase RL00481 glutamate decarboxylase gama-amino butrylic acid (GABA) production 4.1.1.15 Rat 10116 Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Human Diseases:Metabolic Disorders:Type I diabetes mellitus:map04940#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650#Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 2180326,1976015,2735448, Changes in the activity of glutamate decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid synthesis, in response to insulin-induced hypoglycemia were measured in several brain areas involved in glucoregulation[2180326]#We have studied the regulation of the mRNA encoding one such protein, glutamate decarboxylase (GAD), the rate limiting enzyme of GABA synthesis, after a unilateral lesion in the hippocampus that leads to increased seizure susceptibility[1976015]#Rates for glucose flux through the GABA shunt and glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, were measured in ventro-medial nucleus (VMN) and lateral hypothalamic (LHA) homogenates[2735448]# A pyridoxal-phosphate protein. The brain enzyme also acts on L-cysteate, 3-sulfino-L-alanine and L-aspartate. glutamate decarboxylase RL00482 phosphatidylinositol phosphate kinase PA biosynthesis 2.7.1.68 Rat 10116 Cellular Processes:Cell Motility:Regulation of actin cytoskeleton:map04810#Environmental Information Processing:Signal Transduction:Phosphatidylinositol signaling system:map04070#Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562# 8190262, As phosphatidylinositol 4-kinase is the rate-limiting enzyme for the production of phosphatidylinositol 4,5-bisphosphate, which is the preferred substrate for phospholipase C, we investigated the expression of phosphatidylinositol 4-kinase messenger RNA[8190262]# This enzyme can also phosphorylate PtdIns3P in the 4-position, and PtdIns, PtdIns3P and PtdIns(3,4)P2 in the 5-position in vitro, but to a lesser extent. The last of these reactions occurs in vivo and is physiologically relevant. Three different isoforms are known. 1-phosphatidylinositol-4-phosphate 5-kinase RL00483 xanthine oxidoreductase purine catabolism 1.17.1.4 Mouse 10090 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230# 12502743, Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism occurring in most cell types[12502743]# Acts on a variety of purines and aldehydes, including hypoxanthine. The enzyme from eukaryotes contains [2Fe-2S], FAD and a molybdenum centre. The animal enzyme can be interconverted to EC 1.17.3.2, xanthine oxidase (the oxidase form). That from liver exists in vivo mainly in the dehydrogenase form, but can be converted into EC 1.17.3.2 by storage at -20 _degree_C, by treatment with proteolytic agents or organic solvents, or by thiol reagents such as Cu2+, N-ethylmaleimide or 4-mercuribenzoate. The effect of thiol reagents can be reversed by thiols such as 1,4-dithioerythritol. This enzyme can also be converted into EC 1.17.3.2 by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide. In other animal tissues, the enzyme exists almost entirely as EC 1.17.3.2, but can be converted into the dehydrogenase form by 1,4-dithioerythritol. xanthine dehydrogenase RL00484 pyroglutamyl aminopeptidase I 3.4.19.6 Rat 10116 7494810, This tripeptide, a potential prodrug of L-Dopa, is absorbed by the intestinal peptide transporter, is relatively stable in the gut wall, and is converted to L-Dopa by peptidases with the cleavage by pyroglutamyl aminopeptidase I to L-Dopa-Pro as the rate limiting step[7494810]# Highly specific for thyrotropin releasing hormone (pyroglutamyl-histidyl-prolylamide). Will not cleave the pyroglutamyl-histidyl bond of luteinizing hormone releasing hormone. Found in serum and brain. Inhibited by metal chelators. In peptidase family M1 (membrane alanyl aminopeptidase family) pyroglutamyl-peptidase II RL00486 gamma-glutamyl phosphate reductase proline biosynthesis 1.2.1.38 Yeast 4932 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 14602584, These results indicate that both enzymes, not Delta(1)-pyrroline-5-carboxylate reductase, are rate-limiting enzymes in yeast cells[14602584]# N-acetyl-gamma-glutamyl-phosphate reductase RL00487 citrate lyase de novo synthesis of fatty acids and triglycerides 2.3.3.8 Rat 10116 Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 3108130, The effect of thyroparathyroidectomy (TPTX) on ATP citrate lyase regulation, a rate-limiting enzyme of fatty acid synthesis in hepatic cytosol, was investigated in rats refed after a 24 h fast[3108130]# The enzyme can be dissociated into components, two of which are identical with EC 4.1.3.34 (citryl-CoA lyase) and EC 6.2.1.18 (citrate---CoA ligase). ATP citrate synthase RL00488 malate dehydrogenase the NADH shuttle that produces ATP in glucose metabolism 1.1.1.37 Rat 10116 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glyoxylate and dicarboxylate metabolism:map00630#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Energy Metabolism:Carbon fixation:map00710# 8624506, In addition a more active malate-aspartate shuttle, which in heart provides the major route for transfer of reducing equivalents to the mitochondria, was suggested by elevated levels of the cytosolic isoenzyme of aspartate aminotransferase; malate dehydrogenase did not increase but the activity of this enzyme is very high and unlikely to be rate-limiting in the shuttle[8624506]# Also oxidizes some other 2-hydroxydicarboxylic acids. malate dehydrogenase RL00489 pyruvoyl tetrahydropterin synthase synthesizing BH4/the synthesis of human tetrahydrobiopterin 4.2.3.12 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 11778454, Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase[11778454]# Catalyses triphosphate elimination and an intramolecular redox reaction in the presence of Mg2+. It has been identified in human liver. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 3.5.4.16 (GTP cyclohydrolase I) [3]. 6-pyruvoyltetrahydropterin synthase RL00490 Indoleamine 2,3-dioxygenase the kynurenine pathway of tryptophan metabolism/UV filter biosynthesis 1.13.11.52 Mouse 10090 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 17055065, Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the tryptophan catabolism, has been shown to play an important role in various forms of immune tolerance[17055065]# A protohemoprotein. Requires ascorbic acid and methylene blue for activity. This enzyme has broader substrate specificity than EC 1.13.11.11, tryptophan 2,3-dioxygenase [1]. It is induced in response to pathological conditions and host-defense mechanisms and its distribution in mammals is not confined to the liver [2]. While the enzyme is more active with D-tryptophan than L-tryptophan, its only known function to date is in the metabolism of L-tryptophan [2,6]. Superoxide radicals can replace O2 as oxygen donor [4,7]. indoleamine 2,3-dioxygenase RL00491 fatty acid synthase fatty acid biosynthetic pathway 2.3.1.85 Mouse 10090 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 17409402,17694178,18285497, As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased[17409402]#Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition[17694178]#Fatty acid synthase and steaoryl-coenzyme A desaturase, the two rate-limiting enzymes in lipogenesis, were upregulated in neoplastic relative to dysplastic livers[18285497]# The animal enzyme is a multi-functional protein catalysing the reactions of EC 2.3.1.38 [acyl-carrier-protein] S-acetyltransferase, EC 2.3.1.39 [acyl-carrier-protein] S-malonyltransferase, EC 2.3.1.41 3-oxoacyl-[acyl-carrier-protein] synthase, EC 1.1.1.100 3-oxoacyl-[acyl-carrier-protein] reductase, EC 4.2.1.61 3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase, EC 1.3.1.10 enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) and EC 3.1.2.14 oleoyl-[acyl-carrier-protein] hydrolase. fatty-acid synthase RL00492 enolase glycolytic pathway 4.2.1.11 Rat 10116 Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010# 15459207, A protein with a molecular mass of 52 kDa that is strongly induced by ERK1/2 activation in response to ischemic hypoxia and reoxygenation was identified as alpha-enolase, a rate-limiting enzyme in the glycolytic pathway, by liquid chromatography-mass spectrometry and amino acid sequencing[15459207]# Also acts on 3-phospho-D-erythronate. phosphopyruvate hydratase RL00493 spermidine/spermine N-acetyltransferase the polyamine catabolic pathway 2.3.1.57 Mouse 10090 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220# 15737201, Overexpression of the rate-limiting enzyme in polyamine catabolism spermidine/spermine N1-acetyltransferase (SSAT) in transgenic (Tg) mouse leads to accumulation of putrescine in the skin and permanent hair loss at the age of 3 wk[15737201]# Acts on propane-1,3-diamine, pentane-1,5-diamine, putrescine, spermidine (forming N1- and N8-acetylspermidine), spermine, N1-acetylspermidine and N8-acetylspermidine. diamine N-acetyltransferase RL00494 leukotriene a4 hydrolase biosynthesis of leukotriene B4 3.3.2.6 Rat 10116 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 12865451, Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis of leukotriene B4 (LTB4), a potent inflammatory mediator[12865451]# This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.2.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [3]. leukotriene-A4 hydrolase RL00495 leukotriene a4 hydrolase biosynthesis of leukotriene B4 3.3.2.6 Mouse 10090 Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 12139459, The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4)[12139459]# This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.2.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [3]. leukotriene-A4 hydrolase RL00496 phosphoenolpyruvate carboxykinase (GTP) Glyceroneogenesis 4.1.1.32 Mouse 10090 Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 8751724,7799943,11557984, Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver[8751724]#This enzyme catalyzes the rate-limiting step in hepatic and renal gluconeogenesis and adipose glyceroneogenesis[7799943]#In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis[11557984]# ITP can act as phosphate donor. phosphoenolpyruvate carboxykinase (GTP) RL00497 histidine decarboxylase histamine synthesis 4.1.1.22 Mouse 10090 Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340# 15114681,11827977,10843737,17158962,17360717,12875237, Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production[10843737]#Based on this analogy, we investigated the expression of histidine decarboxylase (HDC), the rate-limiting enzyme of histamine synthesis, in mouse male germ cells[11827977]#Infiltrating polymorphonuclear leukocytes (PMN) in the peritoneal cavity were found to express L-histidine decarboxylase (HDC), the rate-limiting enzyme of histamine synthesis, in a csein-induced peritonitis model[15114681]#We have studied histidine decarboxylase (HDC), the rate-limiting enzyme for mammalian histamine synthesis[12875237]# A pyridoxal-phosphate protein (in animal tissues). The bacterial enzyme has a pyruvoyl residue as prosthetic group. histidine decarboxylase RL00498 dihydropyrimidine dehydrogenase 5-fluorouracil (5-FU) chemotherapy catabolic pathway 1.3.1.2 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 15025949,12527935,9914783,9597696,12651209,12104082,11376565, The administered 5-FU is degraded mainly in the liver by dihydropyrimidine dehydrogenase (DPD), which is the initial rate-limiting enzyme in the catabolic pathway of pyrimidine[12527935]#BACKGROUND & OBJECTIVE: Anti-cancer effect of 5-Fluorouracil (5-FU) is mediated mainly by inhibition of the thymidylate synthase (TS), while dihydropyrimidine dehydrogenase (DPD) is an initial and a rate-limiting catabolic enzyme of 5-FU[15025949]#Protein levels and gene expression of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for degradation of 5-fluorouracil, were studied in two human tumor cell lines (fibrosarcoma HT-1080 and pancreatic carcinoma MIAPaCa-2) in various growth phases of the cultured cells and of tumor xenografts implanted into nude mice[9914783]#Interspecies differences in dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme in pyrimidine degradation, were assessed in cytosol from livers isolated from human, monkey, dog, rat, and mouse[9597696]#The circadian-dependent efficacy and toxicity of 5-FU are related to the circadian variation in the activity of dihydropyrimidine dehydrogenase (DPD), which is a rate-limiting enzyme in the pyrimidine catabolic pathway[11376565]#BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in catabolism of pyrimidines including 5-fluorouracil[12104082]#Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism[12651209]# Also acts on dihydrothymine. dihydropyrimidine dehydrogenase (NADP+) RL00499 aromatic amino acid decarboxylase renal dopamine formation 4.1.1.28 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Histidine metabolism:map00340#Metabolism:Amino Acid Metabolism:Phenylalanine metabolism:map00360#Metabolism:Biosynthesis of Secondary Metabolites:Alkaloid biosynthesis I:map00950#Metabolism:Biosynthesis of Secondary Metabolites:Indole and ipecac alkaloid biosynthesis:map00901#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350# 12235825,15684695,16164646,15927700, The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L-DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine[15684695]#Three enzymes are necessary for efficient dopamine synthesis: tyrosine hydroxylase (TH) converts tyrosine to L-DOPA, aromatic L-amino acid decarboxylase (AADC) then converts L-DOPA to dopamine, and guanosine triphosphate cyclohydrolase I (GCH) is the rate-limiting enzyme for the synthesis of TH co-factor tetrahydrobiopterine[12235825]#In tubules preincubated with inhibitors of aromatic amino acid decarboxylase (AADC), the rate-limiting enzyme in renal dopamine formation, prolactin had no effect on Na(+), K(+)-ATPase activity[16164646]#Tyrosine hydroxylation, the rate-limiting step in CA synthesis, was assessed by measuring the accumulation of 3,4-dihydroxyphenyalanine (DOPA) by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC) in rat striatal dices following incubation of the tissue with the aromatic L-amino acid decarboxylase inhibitor m-hydroxybenzyl hydrazine (NSD 1015)[15927700]# A pyridoxal-phosphate protein. The enzyme also acts on some other aromatic L-amino acids, including L-tryptophan. aromatic-L-amino-acid decarboxylase RL00500 acetyl CoA carboxylase the de novo synthesis of lipids and cholesterol 6.4.1.2 Mouse 10090 Metabolism:Biosynthesis of Secondary Metabolites:Tetracycline biosynthesis:map00253#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Lipid Metabolism:Fatty acid biosynthesis:map00061# 8938993, However, since it is unknown whether peroxisome proliferators have an effect on biosynthesis of fatty acid or not, we commenced to study if acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis, is inhibited by 2-(p-chlorophenoxy)-2-methylpropionic acid or 2-ethylhexanoic acid which is a typical peroxisome proliferator[8938993]# A biotinyl-protein. Also catalyses transcarboxylation; the plant enzyme also carboxylates propanonyl-CoA and butanoyl-CoA. acetyl-CoA carboxylase RL00501 l kynurenine hydroxylase tryptophan-NAD pathway in Saccharomyces carlsbergensis 1.14.13.9 Rat 10116 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 7131097, As kynurenine 3-hydroxylase is reported to be a rate-limiting enzyme in the tryptophan-NAD pathway in rats, branched chain amino acids, branched chain alpha-keto acids and several other keto acids were tested for their effects on kynurenine 3-hydroxylase activity in the mitochondrial outer membrane fraction prepared from rat liver[7131097]# A flavoprotein (FAD). kynurenine 3-monooxygenase RL00502 cytoplasmic acetyl coenzyme A [CoA] synthetase the de novo synthesis of lipids and cholesterol 6.2.1.1 Mouse 10090 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Propanoate metabolism:map00640#Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010# 2902801, Enzymes likely to be rate limiting to this process include acetyl CoA carboxylase, fatty acid synthetase, acetyl CoA synthetase, and/or pyruvate dehydrogenase[2902801]# Also acts on propanoate and propenoate. acetate---CoA ligase RL00504 citrate lyase de novo synthesis of fatty acids and triglycerides 2.3.3.8 Mouse 10090 Metabolism:Energy Metabolism:Reductive carboxylate cycle (CO2 fixation):map00720#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020# 17404227, This phenotype is caused by a mild but significant reduction in total energy expenditure paralleled by increased expression of ATP citrate lyase, a rate-limiting step in de novo synthesis of fatty acids and triglycerides[17404227]# The enzyme can be dissociated into components, two of which are identical with EC 4.1.3.34 (citryl-CoA lyase) and EC 6.2.1.18 (citrate---CoA ligase). ATP citrate synthase RL00505 uroporphyrinogen synthase porphyrin synthesis 2.5.1.61 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 7326026, The results show that the rate-limiting enzyme for the hepatic conversion of 5-aminolaevulinate into protoporphyrin is porphobilinogen deaminase[7326026]# The enzyme works by stepwise addition of pyrrolylmethyl groups until a hexapyrrole is present at the active centre. The terminal tetrapyrrole is then hydrolysed to yield the product, leaving a cysteine-bound dipyrrole on which assembly continues. In the presence of a second enzyme, EC 4.2.1.75 uroporphyrinogen-III synthase, which is often called cosynthase, the product is cyclized to form uroporphyrinogen-III. If EC 4.2.1.75 is absent, the hydroxymethylbilane cyclizes spontaneously to form uroporphyrinogen I. hydroxymethylbilane synthase RL00506 uroporphyrinogen synthase porphyrin synthesis 2.5.1.61 Yeast 4932 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 14559249, In an attempt to identify rate-limiting steps in heme synthesis, which may constitute potential regulatory points, we constructed yeast strains overproducing two enzymes of the pathway: the porphobilinogen synthase (PBG-S) and deaminase (PBG-D)[14559249]# The enzyme works by stepwise addition of pyrrolylmethyl groups until a hexapyrrole is present at the active centre. The terminal tetrapyrrole is then hydrolysed to yield the product, leaving a cysteine-bound dipyrrole on which assembly continues. In the presence of a second enzyme, EC 4.2.1.75 uroporphyrinogen-III synthase, which is often called cosynthase, the product is cyclized to form uroporphyrinogen-III. If EC 4.2.1.75 is absent, the hydroxymethylbilane cyclizes spontaneously to form uroporphyrinogen I. hydroxymethylbilane synthase RL00507 glucose phosphate adenylyltransferase bacterial glycogen synthesis 2.7.7.27 E.coli 83333 Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500# 381303,2981798,224050, We suggest that this difference reflects a change in the steady state level of a previously unknown effector of ADP-glucose synthetase (glucose 1-phosphate adenylyltransferase, EC 2.7.7.27) the rate-limiting enzyme of bacterial glycogen synthesis[381303]#In all of the metabolic conditions studied in this report the adenylate energy charge ((ATP + 1/2 ADP)/(ATP + ADP + AMP)) and the level of the rate-limiting enzyme of glycogen synthesis, ADP-glucose synthetase (glucose 1-phosphate adenylyltransferase, EC 2.7.7.27), were the same[224050]#We also show that physiological concentrations of GTP inhibit ADP-glucose synthetase (glucose-1-phosphate adenylyltransferase, EC 2.7.7.27), the rate-limiting enzyme of bacterial glycogen synthesis, in vitro[2981798]# glucose-1-phosphate adenylyltransferase RL00508 hexokinase glycolysis 2.7.1.1 Mouse 10090 Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 8375589,10428828, This enzyme mediates the rate-limiting step in brain glucose metabolism, namely the intracellular conversion of glucose to glucose-6-phosphate[8375589]#Hexokinase II is primarily expressed in muscle and adipose tissues where it catalyzes the phosphorylation of glucose to glucose 6-phosphate, a possible rate-limiting step for glucose disposal[10428828]# D-Glucose, D-mannose, D-fructose, sorbitol and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. hexokinase RL00509 oxoglutarate dehydrogenase complex citric acid cycle 1.2.4.2/2.3.1.61/1.8.1.4 Mouse 10090 Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Lysine degradation:map00310#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252# 8267405,15466852, The measured rate of glutamine transport into the cells approximated to the metabolic flux and is suggested as a rate-limiting step[8267405]#The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the alpha-ketoglutarate dehydrogenase complex) is a rate-limiting enzyme in the mitochondrial Krebs cycle[15466852]# A multimer (24-mer) of this enzyme forms the core of the multienzyme complex, and binds tightly both EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively succinylated by EC 1.2.4.2, and the only observed direction catalysed by EC 2.3.1.61 is that where this succinyl group is passed to coenzyme A. dihydrolipoyllysine-residue succinyltransferase RL00510 glutamyl tRNA reductase heme biosynthesis 1.2.1.70 E.coli 83333 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 16122943, In the present work, we construct the helper plasmid pHg expressing glutamyl-tRNA reductase (hemA) a key enzyme catalyzing the rate-limiting reaction in heme biosynthesis in E[16122943]# This enzyme forms part of the pathway for the biosynthesis of 5-aminolevulinate from glutamate, known as the C5 pathway. The route shown in the diagram is used in most eubacteria, and in all archaebacteria, algae and plants. However, in the alpha-proteobacteria, EC 2.3.1.37, 5-aminolevulinate synthase, is used in an alternative route to produce the product 5-aminolevulinate from succinyl-CoA and glycine. This route is found in the mitochondria of fungi and animals, organelles that are considered to be derived from an endosymbiotic alpha-proteobacterium. Although higher plants do not possess EC 2.3.1.37, the protistan Euglena gracilis possesses both the C5 pathway and EC 2.3.1.37. glutamyl-tRNA reductase RL00511 glucokinase glucose metabolism 2.7.1.2 Rat 10116 Human Diseases:Metabolic Disorders:Type II diabetes mellitus:map04930#Cellular Processes:Endocrine System:Insulin signaling pathway:map04910#Metabolism:Carbohydrate Metabolism:Starch and sucrose metabolism:map00500#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Human Diseases:Metabolic Disorders:Maturity onset diabetes of the young:map04950#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 16921397,10593862,10905475,10433237,8020491, BACKGROUND AND PURPOSE: Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in beta-cells[16921397]#We conclude that restricted expression of GK in muscle leads to an enhanced capacity for muscle glucose disposal and whole body glucose tolerance under conditions of maximal glucose-insulin stimulation, suggesting that under these conditions glucose phosphorylation becomes rate-limiting[10593862]#Glucokinase (GK) is the rate-limiting enzyme in the glycolytic pathway of the beta-cell and, even in the rat fetus at 22-days gestation, immediately before birth, acts as a sensor of glucose influencing the rate of glucose utilization[10433237]#In pancreatic beta-cells, glucokinase (GK), the rate-limiting enzyme in glycolysis, mediates glucose-induced insulin release by regulating intracellular ATP production[10905475]#These results suggest that glucose phosphorylation is rate limiting for glucose uptake and utilization in FTO-2B and H4IIE cells[8020491]# A group of enzymes found in invertebrates and microorganisms that are highly specific for glucose. glucokinase RL00513 l gulono lactone oxidase ascorbate synthesis 1.1.3.8 Mouse 10090 Metabolism:Carbohydrate Metabolism:Ascorbate and aldarate metabolism:map00053# 16632110,16177205, When mice deficient in L-gulono-gamma-lactone oxidase (Gulo(-/-)), the rate-limiting enzyme in ascorbate synthesis, were depleted of ascorbate and infected with K[16632110]#LPS decreased gulonolactone oxidase activity, which is rate-limiting for de novo synthesis of ascorbate from glucose, but increased the rate of DHAA reduction to ascorbate[16177205]# A microsomal flavoprotein (FAD). The product spontaneously isomerizes to L-ascorbate. While most higher animals can synthesize asborbic acid, primates and guinea pigs cannot [3]. L-gulonolactone oxidase RL00514 HMG CoA synthase mevalonate pathway/ketogenesis 2.3.3.10 Rat 10116 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Lipid Metabolism:Synthesis and degradation of ketone bodies:map00072#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 475, The activity of the rate-limiting enzyme of liver ketone body production, hydroxymethylglutaryl CoA synthetase (HMG CoA synthetase), was not greatly influenced by training or exhuastive exercise indicating that the metabolic control of the ketosis of exercise may more likely be a function of the supply of fatty acids to the liver rather than the activity of HMG CoA synthetase[475]# hydroxymethylglutaryl-CoA synthase RL00515 HMG CoA synthase mevalonate pathway/ketogenesis 2.3.3.10 Mouse 10090 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Lipid Metabolism:Synthesis and degradation of ketone bodies:map00072#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 11485325,16101500, This SREBP activation covers not only rate-limiting enzymes such as HMG CoA synthase and reductase that have been well established as SREBP targets, but also all the enzyme genes in the cholesterol synthetic pathway tested here[11485325]#The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase)[16101500]# hydroxymethylglutaryl-CoA synthase RL00516 N-acetyltransferase melatonin synthesis 2.3.1.5 Mouse 10090 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232#Metabolism:Xenobiotics Biodegradation and Metabolism:Trinitrotoluene degradation:map00633# 16842546,9597751,9708862,8943074, The synthesis of melatonin is regulated by a rate-limiting enzyme, serotonin N-acetyltransferase (NAT)[9597751]#We recently demonstrated that stimulation of beta-adrenergic receptors only increases nighttime arylalkylamine N-acetyltransferase (Aa-Nat, the rate-limiting enzyme in melatonin synthesis) mRNA levels in mouse pineal gland in vitro, which suggests that pineal clocks may gate Aa-Nat gene expression[16842546]#The enzyme serotonin N-acetyltransferase (NAT) catalyzes the rate limiting step in melatonin synthesis[8943074]#The primary structure of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT: the rate-limiting enzyme in melatonin synthesis) in the mouse retina was deduced from the cDNA nucleotide sequence[9708862]# Wide specificity for aromatic amines, including serotonin; also catalyses acetyl-transfer between arylamines without CoA. arylamine N-acetyltransferase RL00517 GTP cyclohydrolase 1 BH4 synthesis/the biosynthesis of tetrahydrobiopterin (BH(4)),a natural cofactor for tyrosine and tryptophan hydroxylases 3.5.4.16 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 16650618,15684695,16190874, These findings reveal the significance of estrogen in modulating regulation of rate limiting enzyme in the (6R)-5,6,7,8-tetrahydrobiopterin biosynthesis, which may have implications for sex-related differences in vulnerability in related disorders[16650618]#The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L-DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine[15684695]#GTP cyclohydrolase I (GCH) is the first and rate-limiting enzyme in the biosynthesis of 5,6,7,8-tertahydrobiopterin (BH4), the required cofactor for tyrosine hydroxylase[16190874]# The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit; the recyclization may be non-enzymic. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 4.2.3.12 (6-pyruvoyltetrahydropterin synthase) [3]. GTP cyclohydrolase I RL00518 oxygen oxidoreductase leukotriene synthesis/first step in the pathway,but the conversion of LTA4 to LTB4 1.13.11.34 Mouse 10090 Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590# 12142344, 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined[12142344]# arachidonate 5-lipoxygenase RL00519 Heme oxygenase CO generation,degrades heme/production of bilirubin/heme degradation pathway 1.14.99.3 Mouse 10090 Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 18768868, Heme oxygenase (HO)-1 catalyzes the rate-limiting step of heme degradation and plays an important anti-inflammatory role via its enzymatic products carbon monoxide and biliverdin[18768868]# Requires NAD(P)H and EC 1.6.2.4, NADPH---hemoprotein reductase. The terminal oxygen atoms that are incorporated into the carbonyl groups of pyrrole rings A and B of biliverdin are derived from two separate oxygen molecules [4]. The third oxygen molecule provides the oxygen atom that converts the alpha-carbon to CO. The central iron is kept in the reduced state by NAD(P)H. heme oxygenase RL00521 l myo inositol phosphate synthase conversion of D-glucose 6-phosphate to L-myo-inositol 1-phosphate in the inositol biosynthetic pathway 5.5.1.4 Yeast 4932 Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 16453101,14730448, L-myo-inositol 1-phosphate synthase (EC 5.5.1.4; MIPS) catalyzes the first rate limiting conversion of D-glucose 6-phosphate to L-myo-inositol 1-phosphate in the inositol biosynthetic pathway[16453101]#L-myo-inositol 1-phosphate synthase (EC 5.5.1.4; MIPS) catalyzes conversion of glucose 6-phosphate to L-myo-inositol 1-phosphate, the first and the rate-limiting step in the production of inositol, and has been reported from evolutionarily diverse organisms[14730448]# Requires NAD+, which dehydrogenates the -CHOH- group to -CO- at C-5 of the glucose 6-phosphate, making C-6 into an active methylene, able to condense with the -CHO at C-1. Finally, the enzyme-bound NADH reconverts C-5 into the -CHOH- form. inositol-3-phosphate synthase RL00522 sterol 27-hydroxylase the alternative pathway 1.14.13.15 Rat 10116 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 15936349, They are cholesterol 7alpha-hydroxylase (CYP7A1), the rate limiting enzyme in the classic pathway, sterol 12alpha-hydroxylase (CYP8B1), the key enzyme for synthesis of cholic acid (CA), and sterol 27-hydroxylase (CYP27), the initial enzyme in the alternative pathway[15936349]# Requires ferrodoxin. Acts on cholesterol, cholest-5-en-3beta,7alpha-diol, 7alpha-hydroxycholest-4-en-3-one, 5beta-cholestane-3alpha,7alpha-diol as well as 5beta-cholestane-3alpha,7alpha,12alpha-triol. With cholesterol as well as 26-hydroxycholesterol, 24-hydroxy- and 25-hydroxycholesterol are also formed. With prolonged treatment, 26-hydroxycholesterol is converted into the corresponding 27-aldehyde and 27-oic acid. cholestanetriol 26-monooxygenase RL00523 sterol 27-hydroxylase the alternative pathway 1.14.13.15 Mouse 10090 Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 15936349, They are cholesterol 7alpha-hydroxylase (CYP7A1), the rate limiting enzyme in the classic pathway, sterol 12alpha-hydroxylase (CYP8B1), the key enzyme for synthesis of cholic acid (CA), and sterol 27-hydroxylase (CYP27), the initial enzyme in the alternative pathway[15936349]# Requires ferrodoxin. Acts on cholesterol, cholest-5-en-3beta,7alpha-diol, 7alpha-hydroxycholest-4-en-3-one, 5beta-cholestane-3alpha,7alpha-diol as well as 5beta-cholestane-3alpha,7alpha,12alpha-triol. With cholesterol as well as 26-hydroxycholesterol, 24-hydroxy- and 25-hydroxycholesterol are also formed. With prolonged treatment, 26-hydroxycholesterol is converted into the corresponding 27-aldehyde and 27-oic acid. cholestanetriol 26-monooxygenase RL00524 carnitine palmitoyltransferase 1a fatty acid metabolism/fatty acid oxidation 2.3.1.21 Rat 10116 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 12359092, In contrast, phosphatidate phosphohydrolase, the rate-limiting enzyme for TG synthesis, was found to be 20% lower in the livers of the CLA-fed rats[12359092]# Broad specificity to acyl group, over the range C8 to C18; optimal activity with palmitoyl-CoA. cf. EC 2.3.1.7 carnitine O-acetyltransferase and EC 2.3.1.137 carnitine O-octanoyltransferase. carnitine O-palmitoyltransferase RL00525 carnitine palmitoyltransferase 1a fatty acid metabolism/fatty acid oxidation 2.3.1.21 Mouse 10090 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 15044358, To clarify the paradoxic effects of cerulenin, namely its in vitro inhibitory effects on fat catabolism and its in vivo reduction of fat mass, we studied the in vivo and in vitro effects of cerulenin on carnitine palmitoyltransferase-1 (CPT-1) activity, the rate-limiting enzyme of fatty acid oxidation[15044358]# Broad specificity to acyl group, over the range C8 to C18; optimal activity with palmitoyl-CoA. cf. EC 2.3.1.7 carnitine O-acetyltransferase and EC 2.3.1.137 carnitine O-octanoyltransferase. carnitine O-palmitoyltransferase RL00526 Choline-phosphate cytidylyltransferase membrane phospholipid synthesis 2.7.7.15 Rat 10116 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 8255685,6477961,7126613,15574675,9421188,603639,10615073,11097182, The principle rate-limiting enzyme required for phosphatidylcholine production is cytidine 5'-triphosphate:cholinephosphate cytidylyltransferase[8255685]#This is consistent with the idea that the rate-limiting reaction is that catalyzed by cholinephosphate cytidylyltransferase[7126613]#These results indicate that cholinephosphate cytidylyltransferase catalyzes a rate-limiting reaction in phosphatidylcholine formation by fetal rat lung type II cells.[6477961]#Activity of cholinephosphate cytidylyltransferase, the rate-limiting enzyme in phosphatidylcholine synthesis, increases rapidly in the lung after birth predominantly due to an increase in membrane-associated activity[9421188]#The activity of CTP:cholinephosphate cytidylyltransferase (CPCT), the rate-limiting enzyme in phosphatidylcholine synthesis was reduced by approximately 50% by a 1:10 dilution of spore extract[15574675]#An analysis of the available data on the cytidine pathway for the synthesis of phosphatidylcholine and phosphatidylethanolamine, by the logic derived from the theoretical principles of metabolic regulation, shows that the first two reactions catalysed by choline (ethanolamine) kinase and phosphocholine (phosphoethanolamine) cytidylyltransferase are rate-limiting, whereas the phosphocholine (phosphoethanolamine) transferase step is near equilibrium in rat liver.[603639]#The results confirm that CT has a rate-limiting and regulatory role in the synthesis of type II cell DSPC, and raise possibilities for novel therapeutic interventions[10615073]#The activities of the rate-limiting enzymes in the de novo synthesis of PC and PE, CTP:phosphocholine cytidylyltransferase (CT), and CTP:phosphoethanolamine cytidylyltransferase (ET), respectively, were measured in the retinas excised at 5:00, 9:00, 13:00, and 17:00 h from rats adapted to a 24-h cycle with lights on from 7:00 to 19:00 h[11097182]# choline-phosphate cytidylyltransferase RL00527 Choline-phosphate cytidylyltransferase membrane phospholipid synthesis 2.7.7.15 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 11279002,10101264, CTP:phosphocholine cytidylyltransferase (CCT) is the rate-limiting and regulated enzyme of mammalian phosphatidylcholine biosynthesis[11279002]#CTP:phosphocholine cytidylyltransferase (CT) is a rate-limiting and complexly regulated enzyme in phosphatidylcholine (PC) biosynthesis and is important in the adaptation of macrophages to cholesterol loading[10101264]# choline-phosphate cytidylyltransferase RL00528 glycerol phosphate dehydrogenase glycerol phosphate shuttle 1.1.99.5 Mouse 10090 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 12597242, Using the mice that lack mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a rate limiting enzyme of the glycerol-phosphate NADH shuttle, we investigated the role of the NADH shuttle system in amylase secretion in response to acetylcholine (ACh) in pancreatic acinar cells[12597242]# glycerol-3-phosphate dehydrogenase RL00529 CMP-N-acetylneuraminic acid hydroxylase generating Neu5G c 1.14.18.2 Rat 10116 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530# 8195125, From considerations of the effects of the structure of the lactosylceramide molecular species on the Vmax and Km for CMP-N-acetylneuraminic acid, it is likely that LacCer alpha 2,3-ST first binds lactosylceramide and then CMP-N-acetylneuraminic acid and that the rate-limiting step in the reaction is the release of the product GM3[8195125]# This enzyme contains both a Rieske-type [2Fe-2S] cluster and a second iron site. The ferricytochrome b5 produced is reduced by NADH and cytochrome-b5 reductase (EC 1.6.2.2). The enzyme can be activated by Fe2+ or Fe3+. CMP-N-acetylneuraminate monooxygenase RL00530 CMP-N-acetylneuraminic acid hydroxylase generating Neu5G c 1.14.18.2 Mouse 10090 Metabolism:Carbohydrate Metabolism:Aminosugars metabolism:map00530# 8132639, The molecular activity of the enzyme (approximately 500/min) is much lower than that reported for NADH-cytochrome b5 reductase, suggesting that the activity or amount of hydroxylase is rate-limiting in CMP-N-glycolylneuraminic acid (NeuGc) biosynthesis[8132639]# This enzyme contains both a Rieske-type [2Fe-2S] cluster and a second iron site. The ferricytochrome b5 produced is reduced by NADH and cytochrome-b5 reductase (EC 1.6.2.2). The enzyme can be activated by Fe2+ or Fe3+. CMP-N-acetylneuraminate monooxygenase RL00532 aldolase glycolysis 4.1.2.13 Rat 10116 Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose phosphate pathway:map00030#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Energy Metabolism:Carbon fixation:map00710# 8015399, These studies are consistent with the aldolase-catalyzed cleavage of fructose 1-phosphate being rate-limiting in hepatic fructose metabolism, and that the CCl4 and BB treatment modify and inactivate the aldolase enzyme[8015399]# Also acts on (3S,4R)-ketose 1-phosphates. The yeast and bacterial enzymes are zinc proteins. The enzymes increase electron-attraction by the carbonyl group, some (Class I) forming a protonated imine with it, others (Class II), mainly of microbial origin, polarizing it with a metal ion, e.g. zinc. fructose-bisphosphate aldolase RL00533 Inosine monophosphate dehydrogenase the de novo synthesis of guanine nucleotides from IMP 1.1.1.205 Mouse 10090 Metabolism:Nucleotide Metabolism:Purine metabolism:map00230#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983# 16936083,11875050,12944494,12183689,10953035, IMPDH1 is a highly conserved, widely expressed housekeeping gene, the product of which catalyzes the rate-limiting step of de novo guanine synthesis[16936083]#IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides[11875050]#Inosine 5'-monophosphate dehydrogenase (IMPDH) is the critical, rate-limiting enzyme in the de novo biosynthesis pathway for guanine nucleotides[12944494]#Inosine 5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides, which are also synthesized from guanine by a salvage reaction catalyzed by the X chromosome-linked enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT)[10953035]#Inosine 5'-monophosphate dehydrogenase (IMPDH) enzyme catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides[12183689]# The enzyme acts on the hydroxy group of the hydrated derivative of the substrate. IMP dehydrogenase RL00534 spermidine synthase formation of the spermine precursor spermidine from putrescine 2.5.1.16 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Glutathione metabolism:map00480#Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Metabolism of Other Amino Acids:beta-Alanine metabolism:map00410#Metabolism:Amino Acid Metabolism:Methionine metabolism:map00271# 16515550, They are synthesized by a set of specific enzymes in which spermidine synthase is the rate-limiting step catalysing the formation of the spermine precursor spermidine from putrescine[16515550]# This enzyme is not identical with EC 2.5.1.22, spermine synthase. The mammalian enzyme is highly specific but the bacterial enzyme can use other acceptors and can synthesize spermine. spermidine synthase RL00535 diacylglycerol acyltransferase diacylglycerol conversion to triacylglycerol 2.3.1.20 Mouse 10090 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830# 12730219, Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays an important role in dietary fat absorption by catalyzing a rate-limiting step in the re-synthesis of diacylglycerols in enterocytes[12730219]# Palmitoyl-CoA and other long-chain acyl-CoAs can act as donors. diacylglycerol O-acyltransferase RL00536 Beta-site APP cleaving enzyme beta amyloid production 3.4.23.46 Rat 10116 Human Diseases:Neurodegenerative Diseases:Alzheimer's disease:map05010# 18295609,18695518, Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Abeta, is an attractive therapeutic approach for the treatment of AD[18295609]#Beta-site APP cleaving enzyme-1 (BACE-1), is a rate-limiting enzyme for beta amyloid production[18695518]# Suggested to be the major "beta-secretase" responsible for the cleavage of the beta-amyloid precursor protein to form the amyloidogenic beta-peptide that is implicated in the pathology of Alzheimer's disease. In peptidase family A1 but is atypical in containing a C-terminal membrane-spanning domain. memapsin 2 RL00537 aromatase converts testosterone to estradiol 1.14.14.1 Rat 10116 Metabolism:Lipid Metabolism:Androgen and estrogen metabolism:map00150#Metabolism:Xenobiotics Biodegradation and Metabolism:gamma-Hexachlorocyclohexane degradation:map00361#Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Lipid Metabolism:Linoleic acid metabolism:map00591#Metabolism:Lipid Metabolism:Arachidonic acid metabolism:map00590#Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Biosynthesis of Secondary Metabolites:Caffeine metabolism:map00232# 11259506,12706301,11312650,9365209, This is the rate-limiting step in steroid biosynthesis[11259506]#In these studies, several structurally related phthalates (0-200 microM) and Wy-14,643 (0-100 microM) were compared to MEHP for their effects on granulosa cell estradiol production and transcript levels of cytochrome P450 enzyme CYP 19, also known as aromatase (P450arom), the rate-limiting enzyme in the conversion of androgens to estrogens[11312650]#MEHP is a female reproductive toxicant and decreases activity, mRNA, and protein levels of aromatase, the rate-limiting enzyme that converts testosterone to estradiol in ovarian granulosa cells[12706301]#The rate limiting step in estrogen biosynthesis is catalysed by an enzyme complex that includes the aromatase cytochrome P450 (CYP19), and regulation of the synthesis of this steroidogenic P450 is the level at which estrogen synthesis is controlled[9365209]# A group of heme-thiolate proteins (P-450), acting on a wide range of substrates including many xenobiotics, steroids, fatty acids, vitamins and prostaglandins; reactions catalysed include hydroxylation, epoxidation, N-oxidation, sulfooxidation, N-, S- and O-dealkylations, desulfation, deamination, and reduction of azo, nitro and N-oxide groups. Together with EC 1.6.2.4, NADPH---hemoprotein reductase, it forms a system in which two reducing equivalents are supplied by NADPH. Some of the reactions attributed to EC 1.14.15.3, alkane 1-monooxygenase, belong here. unspecific monooxygenase RL00538 pyruvate dehydrogenase complex tricarboxylic acid cycle 1.2.4.1/2.3.1.12/1.8.1.4 Mouse 10090 Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine biosynthesis:map00290#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Citrate cycle (TCA cycle):map00020#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Amino Acid Metabolism:Valine, leucine and isoleucine degradation:map00280#Metabolism:Amino Acid Metabolism:Alanine and aspartate metabolism:map00252#Metabolism:Carbohydrate Metabolism:Butanoate metabolism:map00650# 12663261,17142343, The pyruvate dehydrogenase enzyme complex (PDC) is rate limiting for glucose oxidation in the heart[12663261]#Since an increase in mitochondrial calcium levels leads to activation of the pyruvate dehydrogenase complex (the rate-limiting step for carbohydrate oxidation), the increased glucose utilization observed in isolated perfused hearts in the SERCA group may reflect a higher level of mitochondrial calcium[17142343]# A multimer (24-mer or 60-mer, depending on the source) of this enzyme forms the core of the pyruvate dehydrogenase multienzyme complex, and binds tightly both EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively acetylated by EC 1.2.4.1, and the only observed direction catalysed by EC 2.3.1.12 is that where the acetyl group is passed to coenzyme A. dihydrolipoyllysine-residue acetyltransferase RL00539 glycerol phosphate dehydrogenase glycerol phosphate shuttle 1.1.99.5 Rat 10116 Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 8621016,8329724, Mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH) catalyzes a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets[8621016]#It catalyses a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets[8329724]# glycerol-3-phosphate dehydrogenase RL00540 tryptophan 2,3-dioxygenase kynurenine pathway/tryptophan catabolism 1.13.11.11 Mouse 10090 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 11477543,12401474, Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the L-tryptophan-kynurenine pathway, which converts an essential amino acid, L-tryptophan, to N-formylkynurenine[11477543]#This enzyme is inducible by cytokines such as interferon-gamma (IFN-gamma) and is the first and rate-limiting enzyme of the catabolism pathway of tryptophan[12401474]# A protohemoprotein. In mammals, the enzyme appears to be located only in the liver. This enzyme, together with EC 1.13.11.52, indoleamine 2,3-dioxygenase, catalyses the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism [5]. The enzyme is specific for tryptophan as substrate, but is far more active with L-tryptophan than with D-tryptophan [2]. tryptophan 2,3-dioxygenase RL00541 5-aminolevulinate synthase hepatic heme biosynthesis 2.3.1.37 Rat 10116 Metabolism:Amino Acid Metabolism:Glycine, serine and threonine metabolism:map00260#Metabolism:Metabolism of Cofactors and Vitamins:Porphyrin and chlorophyll metabolism:map00860# 16122419,18657588,15181459,16181105,17761694,17537461, We show that the rate-limiting enzyme in hepatic heme biosynthesis, 5-aminolevulinate synthase (ALAS-1), is regulated by the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha)[16122419]#The first and rate-limiting step of heme biosynthesis is catalyzed by ALA synthase (ALA-S), the activity of which was determined in rat aorta using a radiometric assay, approximately 250 nmol x (g wet mass)(-1) x h(-1)[15181459]#In this study, we examined expression of HO-1 as well as non-specific delta-aminolevulinate synthase (ALAS1), the rate-limiting enzyme in heme catabolism and biosynthesis, respectively, in a rat model of PH produced by subcutaneous injection of MCT (60 mg/kg)[16181105]# A pyridoxal-phosphate protein. The enzyme in erythrocytes is genetically distinct from that in other tissues. 5-aminolevulinate synthase RL00542 thymidine kinase synthesis of dTTP/the salvage pathway of nucleotide metabolism 2.7.1.21 Rat 10116 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 8504424,8878781, Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), is the rate-limiting enzyme in the pyrimidine catabolic pathway and has been shown to be the key enzyme in FdUrd catabolism[8504424]#METHODS/RESULTS: Incubation of [14C]-thymidine with mouse liver extracts revealed that addition of taurocholate to the reaction medium induced significant dose-dependent inhibition in the activity of the salvage nucleotide pathway rate-limiting enzyme, thymidine kinase, while other steps of nucleotide metabolism machinery, such as the rate-limiting enzyme of de novo deoxyribonucleotide synthesis, ribonucleotide reductase and the rate-limiting enzyme of thymidine catabolism, dihydropyrimidine dehydrogenase were found to be insensitive to inhibition by taurocholate[8878781]# Deoxyuridine can also act as acceptor, and dGTP can act as a donor. The deoxypyrimidine kinase complex induced by Herpes simplex virus catalyses this reaction as well as those of EC 2.7.1.114 (AMP---thymidine kinase), EC 2.7.1.118 (ADP---thymidine kinase) and EC 2.7.4.9 (dTMP-kinase). thymidine kinase RL00543 Uridine-cytidine nucleoside kinase pyrimidine-nucleotide salvage pathway 2.7.1.48 Mouse 10090 Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - other enzymes:map00983#Metabolism:Nucleotide Metabolism:Pyrimidine metabolism:map00240# 9799561,8951040, Uridine kinase is the rate-limiting enzyme in the salvage pathway for uridine or cytidine of mammalian cells[9799561]#Uridine kinase is the rate-limiting enzyme in the pyrimidine salvage pathway of all mammalian cells[8951040]# Cytidine can act as acceptor; GTP and ITP can act as donors. uridine kinase RL00544 phosphoethanolamine cytidylyltransferase phosphatidylethanolamine synthesis 2.7.7.14 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Aminophosphonate metabolism:map00440#Metabolism:Lipid Metabolism:Glycerophospholipid metabolism:map00564# 11521967, Proposed iPLA2beta functions include participation in phosphatidylcholine (PC) homeostasis by degrading excess PC generated in CHO cells that overexpress CTP:phosphocholine cytidylyltransferase (CT), which catalyzes the rate-limiting step in PC biosynthesis; participation in biosynthesis of arachidonate-containing PC species in P388D1 cells by generating lysophosphatidylcholine (LPC) acceptors for arachidonate incorporation; and participation in signaling events in insulin secretion from islet beta-cells[11521967]# ethanolamine-phosphate cytidylyltransferase RL00546 sulfoalanine decarboxylase the biosynthesis of taurine 4.1.1.29 Mouse 10090 Metabolism:Metabolism of Other Amino Acids:Taurine and hypotaurine metabolism:map00430# 16252094,11997111,14553911, Cysteine sulfinate decarboxylase (CSD) is the rate-limiting biosynthetic enzyme of taurine, but it is still controversial whether the male reproductive organs have the function to synthesize taurine through CSD pathway[16252094]#Cysteine sulfinic acid decarboxylase (CSD) is the rate-limiting enzyme for biosynthesis of taurine which is essential to biological processes such as development of the brain and eye, reproduction, osmoregulation as well as the anti-inflammatory activity of leukocytes[11997111]#Cysteine sulfinic acid decarboxylase, a rate-limiting enzyme for taurine biosynthesis, has been cloned and sequenced in the mouse, rat and human[14553911]# A pyridoxal-phosphate protein. Also acts on L-cysteate. The 1992 edition of the Enzyme List erroneously gave the name sulfoalanine decarboxylase to this enzyme. sulfinoalanine decarboxylase RL00547 pyruvoyl tetrahydropterin synthase synthesizing BH4/the synthesis of human tetrahydrobiopterin 4.2.3.12 Rat 10116 Metabolism:Metabolism of Cofactors and Vitamins:Folate biosynthesis:map00790# 8307017, 6-Pyruvoyl-tetrahydropterin synthase is the rate-limiting enzyme in the synthesis of human tetrahydrobiopterin, a cofactor for several hydroxylases involved in catecholamine and serotonin biosynthesis[8307017]# Catalyses triphosphate elimination and an intramolecular redox reaction in the presence of Mg2+. It has been identified in human liver. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 3.5.4.16 (GTP cyclohydrolase I) [3]. 6-pyruvoyltetrahydropterin synthase RL00548 l myo inositol phosphate synthase inositol biosynthesis 5.5.1.4 Rat 10116 Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 15576064, CONCLUSIONS: The rate-limiting step of inositol biosynthesis, catalyzed by MIP synthase, is inhibited by VPA; inositol depletion is a first event shown to be common to lithium and VPA[15576064]# Requires NAD+, which dehydrogenates the -CHOH- group to -CO- at C-5 of the glucose 6-phosphate, making C-6 into an active methylene, able to condense with the -CHO at C-1. Finally, the enzyme-bound NADH reconverts C-5 into the -CHOH- form. inositol-3-phosphate synthase RL00549 l myo inositol phosphate synthase inositol biosynthesis 5.5.1.4 Mouse 10090 Metabolism:Carbohydrate Metabolism:Inositol phosphate metabolism:map00562#Metabolism:Biosynthesis of Secondary Metabolites:Streptomycin biosynthesis:map00521# 15576064, CONCLUSIONS: The rate-limiting step of inositol biosynthesis, catalyzed by MIP synthase, is inhibited by VPA; inositol depletion is a first event shown to be common to lithium and VPA[15576064]# Requires NAD+, which dehydrogenates the -CHOH- group to -CO- at C-5 of the glucose 6-phosphate, making C-6 into an active methylene, able to condense with the -CHO at C-1. Finally, the enzyme-bound NADH reconverts C-5 into the -CHOH- form. inositol-3-phosphate synthase RL00550 arachidonyl coA synthetase fatty acid internalization 6.2.1.3 Mouse 10090 Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Cellular Processes:Endocrine System:Adipocytokine signaling pathway:map04920#Cellular Processes:Endocrine System:PPAR signaling pathway:map03320# 15051725, Taken together, these results support the hypotheses that ACSs are rate-limiting for fatty acid internalization and that ACS2 enhances neurite outgrowth by promoting PUFA internalization[15051725]# Acts on a wide range of long-chain saturated and unsaturated fatty acids, but the enzymes from different tissues show some variation in specificity. The liver enzyme acts on acids from C6 to C20; that from brain shows high activity up to C24. long-chain-fatty-acid---CoA ligase RL00551 carbamyl phosphate synthetase urea cycle/urea production 6.3.4.16 Rat 10116 Metabolism:Amino Acid Metabolism:Urea cycle and metabolism of amino groups:map00220#Metabolism:Amino Acid Metabolism:Glutamate metabolism:map00251#Metabolism:Amino Acid Metabolism:Arginine and proline metabolism:map00330#Metabolism:Energy Metabolism:Nitrogen metabolism:map00910# 1828177,3993779, 15-20% of mitochondrial matrix protein, is involved in the entry and rate-limiting step of the urea cycle[1828177]#Ornithine prevented the increase in both normal and hepatectomized rats, suggesting that ornithine was rate limiting for the ornithine carbamoyltransferase (OCT) reaction[3993779]# carbamoyl-phosphate synthase (ammonia) RL00552 Alcohol dehydrogenase the conversion of retinol to retinoic acid 1.1.1.1 Mouse 10090 Metabolism:Xenobiotics Biodegradation and Metabolism:Metabolism of xenobiotics by cytochrome P450:map00980#Metabolism:Metabolism of Cofactors and Vitamins:Retinol metabolism:map00830#Metabolism:Lipid Metabolism:Fatty acid metabolism:map00071#Metabolism:Carbohydrate Metabolism:Glycolysis / Gluconeogenesis:map00010#Metabolism:Amino Acid Metabolism:Tyrosine metabolism:map00350#Metabolism:Xenobiotics Biodegradation and Metabolism:3-Chloroacrylic acid degradation:map00641#Metabolism:Lipid Metabolism:Bile acid biosynthesis:map00120#Metabolism:Xenobiotics Biodegradation and Metabolism:1- and 2-Methylnaphthalene degradation:map00624#Metabolism:Xenobiotics Biodegradation and Metabolism:Drug metabolism - cytochrome P450:map00982# 8621625,8801166,9002638, Some members of the alcohol dehydrogenase (ADH) family catalyze retinol oxidation, the rate-limiting step in RA synthesis[8621625]#The rate-limiting step in RA synthesis is the oxidation of retinol, a reaction that can be catalyzed by alcohol dehydrogenase (ADH)[8801166]#Here we have examined mouse testis and epididymis for the presence of endogenous retinoic acid and for the expression of genes encoding class I and class IV alcohol dehydrogenases (ADH), both of which catalyze retinol oxidation, the rate-limiting step in the conversion of retinol to retinoic acid[9002638]# A zinc protein. Acts on primary or secondary alcohols or hemi-acetals; the animal, but not the yeast, enzyme acts also on cyclic secondary alcohols. alcohol dehydrogenase RL00553 Indoleamine 2,3-dioxygenase the kynurenine pathway of tryptophan metabolism/UV filter biosynthesis 1.13.11.52 Human 9606 Metabolism:Amino Acid Metabolism:Tryptophan metabolism:map00380# 16511306,18274832,16931033,17430106,17644054,17192467,17594069,17227442,17305476, This reaction is the first and the rate-limiting step in the kynurenine pathway, the major Trp catabolic pathway in mammals[16511306]#To identify whether binding of NF-kappaB upstream of the IRF-1 gene is rate-limiting in IRF-1 expression in response to IFN-gamma and TNF-alpha, a proteasome inhibitor was utilized to maintain nuclear translocation of NF-kappaB at constitutive levels; its effect on IRF-1 expression and IDO-specific transcription was evaluated[16931033]# A protohemoprotein. Requires ascorbic acid and methylene blue for activity. This enzyme has broader substrate specificity than EC 1.13.11.11, tryptophan 2,3-dioxygenase [1]. It is induced in response to pathological conditions and host-defense mechanisms and its distribution in mammals is not confined to the liver [2]. While the enzyme is more active with D-tryptophan than L-tryptophan, its only known function to date is in the metabolism of L-tryptophan [2,6]. Superoxide radicals can replace O2 as oxygen donor [4,7]. indoleamine 2,3-dioxygenase RL00556 aldose reductase the polyol pathway 1.1.1.21 Mouse 10090 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 17293845, Has wide specificity. aldehyde reductase RL00557 aldose reductase the polyol pathway 1.1.1.21 Rat 10116 Metabolism:Lipid Metabolism:Glycerolipid metabolism:map00561#Metabolism:Carbohydrate Metabolism:Pyruvate metabolism:map00620#Metabolism:Carbohydrate Metabolism:Fructose and mannose metabolism:map00051#Metabolism:Carbohydrate Metabolism:Pentose and glucuronate interconversions:map00040#Metabolism:Carbohydrate Metabolism:Galactose metabolism:map00052# 10727516, Although aldose reductase (AR), the rate-limiting enzyme in this pathway, is a target for pharmacological intervention of diabetic complications, the clinical efficacy of AR inhibitors has not been consistently proved[10727516]# Has wide specificity. aldehyde reductase