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

Basic Information

Enzyme Number

1.14.13.39

Official Name

nitric-oxide synthase

Name from literature

nitric oxide synthase

Pathway from literature

NO synthesis

Pathway from KEGG

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

Organisms

Human (9606)

Genome localization

17q11.2-q12[4843 ], 7q36[4846 ], 12q24.2-q24.31[4842 ],

Comments

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.

Rate-limiting Description

"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)

Regulatory Information

Upstream transcription factor

6667;2034;3725;1487;3162;1051;404552;2353;6772;2624

Regulatory type

Detail

post translational modification;IFN-gamma(404552)

"IFN-gamma regulates NOS-1 expression through posttranscriptional and posttranslational mechanisms." (14980078)

phosphorylation;

"neuronal nitric-oxide synthase activity through serine 741 phosphorylation is inhibited by Calcium/calmodulin-dependent protein kinase I" (15251453)

others;MDA-7 tumor suppressor

"study demonstrate that expression of the MDA-7 tumor suppressor can negatively regulate iNOS expression in malignant melanoma cell lines" (12533668)

transcriptional factor;"c-Fos(2353),STAT-1(6772)"

"a physical interaction between c-Fos and STAT-1 participates in NOS2 gene transcriptional activation in lung epithelium" (12788789)

others;NF-kappaB

"NF-kappaB activation may play a role in protecting gastric epithelial cells from H. pylori-induced apoptosis by upregulating endogenous inducible nitric oxide synthase." (12919943)

transcriptional factor;CEBPB(1051)

"iNOS transcription involves CCAAT-Enhancer-Binding Protein-beta binding to a promoter response element in liver cells." (12958187)

feedback;

"evidence presented that PARP-1 is a novel trans-activator of the iNOS promotor in mesengial cells and that its binding to a specific cis-element of the iNOS promotor appears to be regulated by the end product NO in a feedback inhibition circuit" (16464859)

transcriptional factor;AP-1(3725)

"These findings demonstrate that c-Jun/AP-1 is hepatoprotective during acute hepatitis by regulating nos2/nitric oxide expression and thus functionally antagonizes the cell death-promoting functions of JNK." (17940019)

phosphorylation;

"activity decreases during type I collagen-induced platelet aggregation and may be controlled with differential phosphorylation of specific amino acid residues located in the enzyme" (12379480)

phosphorylation;

"data demonstrate that Rho/ROCK pathway negatively regulates eNOS phosphorylation through inhibition of protein kinase B (PKB), whereas it downregulates eNOS expression independent of PKB." (12446767)

phosphorylation;

"phosphorylation of endothelial nitric oxide synthase at Ser1177 is not sufficient to stimulate NO production in cells cultured at 25 mM glucose" (12644458)

transcriptional factor;HIF-2(2034)

"heNOS is a hypoxia-inducible gene, whose transcription is stimulated through HIF-2 interaction with two contiguous HRE sites located at -5375 to -5366 of the heNOS promoter" (12963737)

phosphorylation;

"Insulin stimulates the formation of NO in human platelets, in the absence of an increase in Ca(2+), by activating PI3-K and AMPK which phosphorylates eNOS on Ser(1177)." (14597982)

phosphorylation;

"Alpha-tocopherol does not affect tetrahydrobiopterin but increased ionomycin-induced eNOS phosphorylation at serine 1177." (15288120)

transcriptional factor;GATA-2(2624)

"The GATA-2 transcription factor interacts with the human eNOS promoter at a region which includes a putative GATA site [-230 to -226]." (7541039)

transcriptional factor;Sp1(6667)

"The Sp1 transcription factor interacts with the human eNOS promoter at a region which includes a putative Sp1 site (-104 to -95). This interaction activates eNOS transcription." (7541039)

phosphorylation;

P29474

phosphorylation;

P29475

phosphorylation;

P35228

phosphorylation;

P29474:from_uniprot:1175_Phosphothreonine

phosphorylation;

P29474:from_uniprot:1177_Phosphoserine

phosphorylation;

P29474:from_uniprot:495_Phosphothreonine

phosphorylation;

P29474:from_uniprot:633_Phosphoserine

phosphorylation;

P29474:from_uniprot:81_Phosphotyrosine

phosphorylation;

P35228:from_uniprot:234_Phosphoserine; by PKA

phosphorylation;

P35228:from_uniprot:578_Phosphoserine; by PKA

phosphorylation;

P35228:from_uniprot:892_Phosphoserine; by PKA

transcriptional factor;CTBP1(1487)

"Binding of neuronal nitric-oxide synthase (nNOS) to carboxyl-terminal-binding protein (CtBP) changes the localization of CtBP from the nucleus to the cytosol: a novel function for targeting by the PDZ domain of nNOS." (11590170)

transcriptional factor;Ctbp1(1487)

"Binding of neuronal nitric-oxide synthase (nNOS) to carboxyl-terminal-binding protein (CtBP) changes the localization of CtBP from the nucleus to the cytosol: a novel function for targeting by the PDZ domain of nNOS." (11590170)

transcriptional factor;HMOX1(3162)

"Interactions between inducible nitric oxide synthase and heme oxygenase-1 in glomerulonephritis." (11849436)

transcriptional factor;SP1(6667)

"Functional analysis of the human endothelial nitric oxide synthase promoter. Sp1 and GATA factors are necessary for basal transcription in endothelial cells." (7541039)

Gene ontology

Gene ontology

GO:0008270 (F) zinc ion binding [P29474, P35228 ];
GO:0033555 (P) multicellular organismal response to stress [P29475 ];
GO:0010523 (P) negative regulation of calcium ion transpor... [P29475 ];
GO:0001974 (P) blood vessel remodeling [P29474 ];
GO:0003785 (F) actin monomer binding [P29474 ];
GO:0042136 (P) neurotransmitter biosynthetic process [P29475 ];
GO:0043542 (P) endothelial cell migration [P29474 ];
GO:0045766 (P) positive regulation of angiogenesis [P29474 ];
GO:0009408 (P) response to heat [P29474, P29475 ];
GO:0050829 (P) defense response to Gram-negative bacterium [P35228 ];
GO:0050796 (P) regulation of insulin secretion [P35228 ];
GO:0006809 (P) nitric oxide biosynthetic process [P29474, P29475, P35228 ];
GO:0001912 (P) positive regulation of leukocyte mediated c... [P35228 ];
GO:0042995 (C) cell projection [P29475 ];
GO:0046870 (F) cadmium ion binding [P29474, P29475 ];
GO:0003100 (P) regulation of systemic arterial blood press... [P29474 ];
GO:0014740 (P) negative regulation of muscle hyperplasia [P29474 ];
GO:0016529 (C) sarcoplasmic reticulum [P29475 ];
GO:0006801 (P) superoxide metabolic process [P35228 ];
GO:0048471 (C) perinuclear region of cytoplasm [P29475 ];
GO:0005634 (C) nucleus [P29474, P35228 ];
GO:0050660 (F) FAD binding [P29474, P29475, P35228 ];
GO:0055117 (P) regulation of cardiac muscle contraction [P29475 ];
GO:0014806 (P) smooth muscle hyperplasia [P29474 ];
GO:0010544 (P) negative regulation of platelet activation [P29474 ];
GO:0005829 (C) cytosol [P29474, P35228 ];
GO:0020037 (F) heme binding [P29474, P29475, P35228 ];
GO:0005509 (F) calcium ion binding [P29474, P35228 ];
GO:0043457 (P) regulation of cellular respiration [P35228 ];
GO:0006527 (P) arginine catabolic process [P29474, P29475, P35228 ];
GO:0009055 (F) electron carrier activity [P29474, P29475, P35228 ];
GO:0001917 (C) photoreceptor inner segment [P29475 ];
GO:0034617 (F) tetrahydrobiopterin binding [P29474, P29475, P35228 ];
GO:0007520 (P) myoblast fusion [P29475 ];
GO:0045909 (P) positive regulation of vasodilation [P29474, P29475 ];
GO:0007005 (P) mitochondrion organization [P29474 ];
GO:0050661 (F) NADP binding [P29474, P29475, P35228 ];
GO:0034618 (F) arginine binding [P29474, P29475, P35228 ];
GO:0001666 (P) response to hypoxia [P29475 ];
GO:0042803 (F) protein homodimerization activity [P35228 ];
GO:0005901 (C) caveola [P29474 ];
GO:0031284 (P) positive regulation of guanylate cyclase ac... [P29474 ];
GO:0008285 (P) negative regulation of cell proliferation [P29474 ];
GO:0004517 (F) nitric-oxide synthase activity [P29474, O75713, P29475, P35228 ];
GO:0051712 (P) positive regulation of killing of cells of ... [P35228 ];
GO:0005506 (F) iron ion binding [P29474, P29475, P35228 ];
GO:0042383 (C) sarcolemma [P29475 ];
GO:0006916 (P) anti-apoptosis [P29474 ];
GO:0005856 (C) cytoskeleton [P29474, P29475 ];
GO:0005516 (F) calmodulin binding [P29474, P29475, P35228 ];
GO:0002227 (P) innate immune response in mucosa [P35228 ];
GO:0055114 (P) oxidation reduction [P29474, O75713, P29475, P35228 ];
GO:0000139 (C) Golgi membrane [P29474 ];
GO:0010181 (F) FMN binding [P29474, P29475, P35228 ];
GO:0034405 (P) response to fluid shear stress [P29474 ];

Tissue expression

Tissue From HPRD

Nervous system [01224 ];
Lung epithelium [01225 ];
Uterus [01225 ];
Eye [01224 ];
Leukocyte [01225 ];
Hepatocyte [01225 ];
Skeletal muscle [01225 ];
Liver [01224 ];
Muscle [01226 ];
Brain [01226, 01225, 01224 ];
B Cell [01225 ];
Uterine myometrium [01225 ];
Platelet [01224 ];
Kidney [01226 ];
Blood vessel [01224 ];
Airway epithelium [01225 ];
Smooth muscle [01225 ];
Monocyte [01225 ];
Endometrium [01225 ];
Neutrophil [01225, 01224 ];
Synovial fluid [01225 ];
Lung [01224 ];
Heart [01226, 01224 ];
Chondrocyte [01225 ];
Dental pulp [01225 ];
Melanocyte [01225 ];
Placenta [01225, 01224 ];
Cerebellum [01225 ];
Retina [01225 ];
Gingival epithelium [01225 ];

Tissue specificity

Platelets, placenta, liver and kidney [P29474 ];

Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland [P29475 ];

Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets [P35228 ];

Subcellular localization

Localization

cell membrane [P29475 ];

myofibril [P29475 ];

golgi apparatus [P29474 ];

cytoskeleton [P29474 ];

membrane [P29474 ];

cytoplasm [P29474 ];

Disease relevance

Disease

Genetic variations in NOS1 gene are associated with susceptibility to infantile hypertrophic pyloric stenosis type 1 (IHPS1) [MIM:179010]. IHPS has an incidence of 1-5 per 1'000 live births in whites and a marked preponderance of males to females (4:1). IHPS is the most frequent disorder requiring surgery in the first year of life. The disorder is characterized by hypertrophy and hyperplasia of the circular muscle layer of the pylorus, leading to persistent vomiting 2-12 weeks after birth. Defective pyloric relaxation and increased pyloric smooth muscle mass have been suggested to be responsible for gastric-outlet obstruction [P29475 ];

Links

SwissProt

O75713; P29474; P29475; P35228

Entrez Gene

4842; 4843; 4846

HPRD

01224; 01225; 01226



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