MetaCyc Enzyme: nNOS

Gene: NOS1 Accession Number: G-8745 (MetaCyc)

Synonyms: nitric-oxide synthase, brain, neural NOS

Species: Homo sapiens

Subunit composition of nNOS = [NOS1]2
         NOS1 monomer = NOS1

Nitric oxide (NO) is the active moiety of the endothelium-derived relaxing factor. In the vasculature NO relaxes smooth muscle and inhibits platelet and leukocyte adhesion. Outside the vasculature, NO participates in the immunologic response to infection and serves as a neurotransmitter.

Nitric oxide synthases (NOSs) are a family of enzymes responsible for the synthesis of nitric oxide from L-arginine and oxygen. The reaction forms citrulline as a by product, which is usually recycled back to arginine for the production of more NO. The three main human NOS enzyme isoforms are nNOS (for neuronal NOS), iNOS (for inducible NOS) and eNOS (for epithelial NOS). They are also known as types I, II and III. These enzymes are well studied, and possess differing cellular distribution and regulatory mechanisms.

All of the isoforms have requirement for multiple factors, including tetrahydrobiopterin [Kwon89, Tayeh89], FMN [Stuehr91], FAD [Stuehr90, Stuehr91], a thiol [Stuehr90] and Ca2+ [Schmidt92]. They all bind the calcium-binding protein calmodulin [Schmidt92, Bredt90] and contain heme [Forstermann94].

nNOS is constitutively expressed and is present in central and peripheral neuronal cells and some epithelial cells. It is regulated by the binding of calmodulin at elevated Ca2+ concentrations. Its functions include long-term regulation of synaptic transmission in the central nervous system, central regulation of blood pressure, smooth muscle relaxation, and vasodilation via peripheral nitrergic nerves [Forstermann94].

Gene Citations: [Nakane93, Hall94]

Molecular Weight of Polypeptide: 160 kD (experimental) [Park96 ]

Unification Links: ArrayExpress:P29475 , Mint:MINT-122019 , ModBase:P29475 , PhosphoSite:P29475 , Pride:P29475 , Protein Model Portal:P29475 , SMR:P29475 , String:9606.ENSP00000320758 , Swiss-Model:P29475 , UniProt:P29475

Relationship Links: Entrez-Nucleotide:PART-OF:U17327 , InterPro:IN-FAMILY:IPR001094 , InterPro:IN-FAMILY:IPR001433 , InterPro:IN-FAMILY:IPR001478 , InterPro:IN-FAMILY:IPR001709 , InterPro:IN-FAMILY:IPR003097 , InterPro:IN-FAMILY:IPR004030 , InterPro:IN-FAMILY:IPR008254 , InterPro:IN-FAMILY:IPR012144 , InterPro:IN-FAMILY:IPR017927 , InterPro:IN-FAMILY:IPR017938 , InterPro:IN-FAMILY:IPR023173 , InterPro:IN-FAMILY:IPR029039 , Panther:IN-FAMILY:PTHR19384:SF5 , Pfam:IN-FAMILY:PF00175 , Pfam:IN-FAMILY:PF00258 , Pfam:IN-FAMILY:PF00595 , Pfam:IN-FAMILY:PF00667 , Pfam:IN-FAMILY:PF02898 , Prints:IN-FAMILY:PR00369 , Prints:IN-FAMILY:PR00371 , Prosite:IN-FAMILY:PS50106 , Prosite:IN-FAMILY:PS50902 , Prosite:IN-FAMILY:PS51384 , Prosite:IN-FAMILY:PS60001 , Smart:IN-FAMILY:SM00228

Gene-Reaction Schematic: ?

Gene-Reaction Schematic

Enzymatic reaction of: nitric-oxide synthase (nNOS)

EC Number:

2 L-arginine + 3 NADPH + H+ + 4 oxygen <=> 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is physiologically favored in the direction shown.

In Pathways: superpathway of L-citrulline metabolism , L-citrulline-nitric oxide cycle

Cofactors or Prosthetic Groups: heme b [Forstermann94], tetrahydrobiopterin [Forstermann94], a thiol [Forstermann94], Ca2+ [Forstermann94], FMN [Forstermann94], FAD [Forstermann94]

Inhibitors (Competitive): N-nitro-L-arginine [Park96]

Kinetic Parameters:

Km (μM)


Blau: Blau N, Bonafe L, Thony B "Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency." Mol Genet Metab 74(1-2);172-85. PMID: 11592814

Bredt90: Bredt DS, Snyder SH (1990). "Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme." Proc Natl Acad Sci U S A 87(2);682-5. PMID: 1689048

Cho98: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1998). "Tepidopterin, 1-O-(L-threo-biopterin-2'-yl)-beta-N-acetylglucosamine from Chlorobium tepidum." Biochim Biophys Acta 1379(1);53-60. PMID: 9468332

Cho99: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1999). "Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum." Biochem J 340 ( Pt 2);497-503. PMID: 10333495

Chung00: Chung HJ, Kim YA, Kim YJ, Choi YK, Hwang YK, Park YS (2000). "Purification and characterization of UDP-glucose:tetrahydrobiopterin glucosyltransferase from Synechococcus sp. PCC 7942." Biochim Biophys Acta 1524(2-3);183-8. PMID: 11113566

Forstermann94: Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994). "Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions." Hypertension 23(6 Pt 2);1121-31. PMID: 7515853

Hall94: Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL, Lu WC, Kau CL, Marsden PA (1994). "Structural organization of the human neuronal nitric oxide synthase gene (NOS1)." J Biol Chem 269(52);33082-90. PMID: 7528745

Kwon89: Kwon NS, Nathan CF, Stuehr DJ (1989). "Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages." J Biol Chem 264(34);20496-501. PMID: 2584226

Maier95: Maier J, Ninnemann H (1995). "Biosynthesis of pteridines in Neurospora crassa, Phycomyces blakesleeanus and Euglena gracilis: detection and characterization of biosynthetic enzymes." Photochem Photobiol 61(1);43-53. PMID: 7899493

Mataga91: Mataga N, Imamura K, Watanabe Y (1991). "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex." Brain Res 551(1-2);64-71. PMID: 1680529

Nakane93: Nakane M, Schmidt HH, Pollock JS, Forstermann U, Murad F (1993). "Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle." FEBS Lett 316(2);175-80. PMID: 7678401

Park96: Park CS, Gianotti C, Park R, Krishna G (1996). "Neuronal isoform of nitric oxide synthase is expressed at low levels in human retina." Cell Mol Neurobiol 16(4);499-515. PMID: 8879752

Schallreuter94: Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler I (1994). "Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin." Science 263(5152);1444-6. PMID: 8128228

Schmidt92: Schmidt HH, Smith RM, Nakane M, Murad F (1992). "Ca2+/calmodulin-dependent NO synthase type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities." Biochemistry 31(12);3243-9. PMID: 1372827

Stuehr90: Stuehr DJ, Kwon NS, Nathan CF (1990). "FAD and GSH participate in macrophage synthesis of nitric oxide." Biochem Biophys Res Commun 168(2);558-65. PMID: 1692211

Stuehr91: Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF (1991). "Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein." Proc Natl Acad Sci U S A 88(17);7773-7. PMID: 1715579

Tanaka89: Tanaka K, Kaufman S, Milstien S (1989). "Tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylases, is synthesized by and regulates proliferation of erythroid cells." Proc Natl Acad Sci U S A 86(15);5864-7. PMID: 2762302

Tayeh89: Tayeh MA, Marletta MA (1989). "Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor." J Biol Chem 264(33);19654-8. PMID: 2584186

Thony00: Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions." Biochem J 347 Pt 1;1-16. PMID: 10727395

Wang11f: Wang H, Yang B, Hao G, Feng Y, Chen H, Feng L, Zhao J, Zhang H, Chen YQ, Wang L, Chen W (2011). "Biochemical characterization of the tetrahydrobiopterin synthesis pathway in the oleaginous fungus Mortierella alpina." Microbiology 157(Pt 11);3059-70. PMID: 21852350

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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