Center for Bioinformatics
Oxidoreductases | Transferases | Hydrolases | Lyases | Isomerases | Ligases

Basic Information

Enzyme Number

1.2.4.1/2.3.1.12/1.8.1.4

Official Name

dihydrolipoyllysine-residue acetyltransferase

Name from literature

pyruvate dehydrogenase complex

Pathway from literature

tricarboxylic acid cycle

Pathway from KEGG

Amino Acid Metabolism; Valine, leucine and isoleucine biosynthesis; map00290

Carbohydrate Metabolism; Pyruvate metabolism; map00620

Carbohydrate Metabolism; Citrate cycle (TCA cycle); map00020

Carbohydrate Metabolism; Glycolysis / Gluconeogenesis; map00010

Amino Acid Metabolism; Glycine, serine and threonine metabolism; map00260

Amino Acid Metabolism; Valine, leucine and isoleucine degradation; map00280

Amino Acid Metabolism; Alanine and aspartate metabolism; map00252

Carbohydrate Metabolism; Butanoate metabolism; map00650

Organisms

Human (9606)

Genome localization

11q23.1[1737 ], Xp22.2-p22.1[5160 ], 3p21.1-p14.2[5162 ], 7q31-q32[1738 ], 4q22-q23[5161 ],

Comments

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.

Rate-limiting Description

"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)

Regulatory Information

Regulatory type

Detail

phosphorylation;

"Short-term elevation in plasma non-esterified fatty acids at rest increases PDH-E1alpha phosphorylation, but exercise overrules this effect and phosphorylation leads to even dephosphorylation during exercise with intralipid infusion." (17065338)

transcriptional factor;

"Only 33% of the functional variants were found in known consensus transcription factor binding sequences or motifs, which suggests that either there are many unknown transcription factor binding motifs or other, unknown mechanisms are involved. The genes with functional polymorphisms that are reported here for the first time include AGTRL2, CAT, CHRNA5, CTSG, CYP2D6, DLD, ERCC1, GABRA1, GABRP, HNRPH3, HIP1, IGKV1-9, KCNJ15, KCNK6, KLK1, MSMB, MYOC, NPY2R, NOTCH4, ORM2, PEDF, PTPRCAP, ST16 (IL24), SULT1A1, and TSHR." (16086313)

phosphorylation;

P08559

phosphorylation;

P11177

phosphorylation;

P29803

phosphorylation;

P10515

phosphorylation;

P08559:from_uniprot:232_Phosphoserine

phosphorylation;

P08559:from_uniprot:289_Phosphotyrosine

phosphorylation;

P08559:from_uniprot:293_Phosphoserine

phosphorylation;

P08559:from_uniprot:295_Phosphoserine

phosphorylation;

P08559:from_uniprot:300_Phosphoserine

phosphorylation;

P08559:from_uniprot:301_Phosphotyrosine

phosphorylation;

P11177:from_uniprot:67_Phosphotyrosine

phosphorylation;

P29803:from_uniprot:230_Phosphoserine

phosphorylation;

P29803:from_uniprot:291_Phosphoserine

phosphorylation;

P29803:from_uniprot:298_Phosphoserine

Gene ontology

Gene ontology

GO:0050660 (F) FAD binding [P09622 ];
GO:0004742 (F) dihydrolipoyllysine-residue acetyltransfera... [Q16791, Q01991, P10515 ];
GO:0006096 (P) glycolysis [P29803, P08559, P10515, P11177 ];
GO:0004148 (F) dihydrolipoyl dehydrogenase activity [P09622 ];
GO:0031405 (F) lipoic acid binding [Q16791, P10515 ];
GO:0006099 (P) tricarboxylic acid cycle [P11177 ];
GO:0009055 (F) electron carrier activity [P09622 ];
GO:0006085 (P) acetyl-CoA biosynthetic process [P10515 ];
GO:0045454 (P) cell redox homeostasis [P09622 ];
GO:0005515 (F) protein binding [P08559, Q01991, P10515 ];
GO:0008152 (P) metabolic process [Q01991 ];
GO:0006090 (P) pyruvate metabolic process [P10515 ];
GO:0005759 (C) mitochondrial matrix [P09622, P29803, P08559, P11177 ];
GO:0004739 (F) pyruvate dehydrogenase (acetyl-transferring... [P29803, P08559, A5YPB6, P11177 ];
GO:0055114 (P) oxidation reduction [P09622, P29803, P08559, A5YPB6, P11177 ];
GO:0005967 (C) mitochondrial pyruvate dehydrogenase complex [P10515 ];

Tissue expression

Tissue From HPRD

Kidney [02420 ];
Heart [01530, 10578, 02420 ];
Skin fibroblast [01530, 02420 ];
Testis [01531 ];
Skin [02420 ];
Liver [01530, 10578, 02420 ];
Skeletal muscle [02420 ];
Brain [02006, 02420 ];

Tissue specificity

Testis. Expressed in postmeiotic spermatogenic cells [P29803 ];

Ubiquitous [P08559 ];

Subcellular localization

Localization

mitochondrion [P09622, P29803, P08559, P10515, P11177 ];

Disease relevance

Disease

Defects in PDHB are a cause of pyruvate dehydrogenase E1 component deficiency (PDHE1 deficiency) [MIM:312170]. PDHE1 deficiency is the most common enzyme defect in patients with primary lactic acidosis. It is associated with variable clinical phenotypes ranging from neonatal death to prolonged survival complicated by developmental delay, seizures, ataxia, apnea, and in some cases to an X-linked form of Leigh syndrome (LS) (Leigh encephalomyelopathy) [P11177 ];

Defects in PDHA1 are a cause of pyruvate decarboxylase E1 component deficiency (PDHE1 deficiency) [MIM:312170]. PDHE1 deficiency is the most common enzyme defect in patients with primary lactic acidosis. It is associated with variable clinical phenotypes ranging from neonatal death to prolonged survival complicated by developmental delay, seizures, ataxia, apnea, and in some cases to an X-linked form of Leigh syndrome (LS) (Leigh encephalomyelopathy) [P08559 ];

Defects in DLD are a cause of congenital infantile lactic acidosis [P09622 ];

Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency [MIM:245348];
also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent [P10515 ];

Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex [P10515 ];

Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600]. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation [P09622 ];

Defects in PDHA1 are the cause of X-linked Leigh syndrome (LS) [MIM:308930]. LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes [P08559 ];

Links

SwissProt

A5YPB6; P08559; P11177; P29803; P09622; P10515; Q01991; Q16791

Entrez Gene

5160; 5161; 5162; 1738; 1737

HPRD

02006; 02420; 10578; 01531; 01530



  Copyright 2009, Center for Bioinformatics 
  Last Modified: 2009-03-24  
  Design by Zhao Min