PROSITE documentation PDOC60001Nitric oxide synthase (NOS) signature
Nitric oxide synthase (EC 1.14.13.39) (NOS) enzymes produce nitric oxide (NO) by catalyzing a five-electron oxidation of a guanidino nitrogen of L-arginine (L-Arg). Oxidation of L-Arg to L-citrulline occurs via two successive monooxygenation reactions producing N(omega)-hydroxy-L-arginine as an intermediate. 2 mol of O(2) and 1.5 mol of NADPH are consumed per mole of NO formed [1].
Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, plants, and bacteria [1]. Best studied are mammals, where three distinct genes encode NOS isozymes: neuronal (nNOS or NOS-1), cytokine-inducible (iNOS or NOS-2) and endothelial (eNOS or NOS-3) [2]. iNOS and nNOS are soluble and found predominantly in the cytosol, while eNOS is membrane associated. The enzymes exist as homodimers, each monomer consisting of two major domains: an N-terminal oxygenase domain, which belongs to the class of heme-thiolate proteins, and a C-terminal reductase domain, which is homologous to NADPH:P450 reductase (EC 1.6.2.4). The interdomain linker between the oxygenase and reductase domains contains a calmodulin (CaM)-binding sequence. NOSs are the only enzymes known to simultaneously require five bound cofactors/prosthetic groups: FAD, FMN, heme, tetrahydrobiopterin and Ca2+-CaM. The animal NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: NADPH --> FAD --> FMN --> heme --> O(2).
eNOS localisation to endothelial membranes is mediated by cotranslational N-terminal myristoylation (see <PDOC00008>) and post-translational palmitoylation [3]. The subcellular localisation of nNOS in skeletal muscle is mediated by anchoring of nNOS to dystrophin. nNOS contains an additional N-terminal domain, the PDZ domain (see <PDOC50106>) [4].
Some bacteria, like Bacillus halodurans, Bacillus subtilis or Deinococcus radiodurans, contain homologs of NOS oxygenase domain.
The pattern is directed against the N-terminal heme binding site.
Expert(s) to contact by email: Last update:December 2001 / First entry.
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PROSITE method (with tools and information) covered by this documentation:
1 | Authors | Liu Q. Gross S.S. |
Title | Binding sites of nitric oxide synthases. | |
Source | Methods Enzymol. 268:311-324(1996). | |
PubMed ID | 8782597 |
2 | Authors | Knowles R.G. Moncada S. |
Title | Nitric oxide synthases in mammals. | |
Source | Biochem. J. 298:249-258(1994). | |
PubMed ID | 7510950 |
3 | Authors | Liu J. Hughes T.E. Sessa W.C. |
Title | The first 35 amino acids and fatty acylation sites determine the molecular targeting of endothelial nitric oxide synthase into the Golgi region of cells: a green fluorescent protein study. | |
Source | J. Cell Biol. 137:1525-1535(1997). | |
PubMed ID | 9199168 |
4 | Authors | Ponting C.P. Phillips C. |
Title | DHR domains in syntrophins, neuronal NO synthases and other intracellular proteins. | |
Source | Trends Biochem. Sci. 20:102-103(1995). | |
PubMed ID | 7535955 |
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