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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Nitric oxide synthases (NOS, E.C. 188.8.131.52) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of L-arginine with the resultant by-product, L-citrulline. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post-translation mechanisms regulating enzyme activity. The nomenclature suggested by NC-IUPHAR of NOS I, II and III  has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C-terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4-dependent reduction of heme bound oxygen for insertion into the substrate, L-arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/calmodulin (CALM2, CALM3, CALM1, P62158) with great avidity and is essentially calcium-independent and constitutively active. Efficient stimulus-dependent coupling of nNOS and eNOS is achieved via subcellular targeting through respective N-terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. L-NAME and related modified arginine analogues are inhibitors of all three isoforms, with IC50 values in the micromolar range.
* Key recommended reading is highlighted with an asterisk
* Alderton WK, Cooper CE, Knowles RG. (2001) Nitric oxide synthases: structure, function and inhibition. Biochem. J., 357 (Pt 3): 593-615. [PMID:11463332]
* Förstermann U, Sessa WC. (2012) Nitric oxide synthases: regulation and function. Eur. Heart J., 33 (7): 829-37, 837a-837d. [PMID:21890489]
* Wang Y, Marsden PA. (1995) Nitric oxide synthases: gene structure and regulation. Adv. Pharmacol., 34: 71-90. [PMID:8562454]
1. Babbedge RC, Bland-Ward PA, Hart SL, Moore PK. (1993) Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br. J. Pharmacol., 110 (1): 225-8. [PMID:7693279]
2. Bland-Ward PA, Moore PK. (1995) 7-Nitro indazole derivatives are potent inhibitors of brain, endothelium and inducible isoforms of nitric oxide synthase. Life Sci., 57 (11): PL131-5. [PMID:7544863]
3. Corbett JA, McDaniel ML. (1992) Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. Diabetes, 41 (8): 897-903. [PMID:1378415]
4. Faraci WS, Nagel AA, Verdries KA, Vincent LA, Xu H, Nichols LE, Labasi JM, Salter ED, Pettipher ER. (1996) 2-Amino-4-methylpyridine as a potent inhibitor of inducible NO synthase activity in vitro and in vivo. Br. J. Pharmacol., 119 (6): 1101-8. [PMID:8937711]
5. Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJ, Knowles RG. (1997) 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J. Biol. Chem., 272 (8): 4959-63. [PMID:9030556]
6. Garvey EP, Oplinger JA, Tanoury GJ, Sherman PA, Fowler M, Marshall S, Harmon MF, Paith JE, Furfine ES. (1994) Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J. Biol. Chem., 269 (43): 26669-76. [PMID:7523409]
7. Mayer B, Hemmens B. (1997) Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem. Sci., 22 (12): 477-81. [PMID:9433128]
8. Moncada S, Higgs A, Furchgott R. (1997) International Union of Pharmacology Nomenclature in Nitric Oxide Research. Pharmacol. Rev., 49 (2): 137-42. [PMID:9228663]
9. Moore WM, Webber RK, Jerome GM, Tjoeng FS, Misko TP, Currie MG. (1994) L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J. Med. Chem., 37 (23): 3886-8. [PMID:7525961]
Database page citation:
Andreas Papapetropoulos, Csaba Szabo, Timothy R. Billiar, Giuseppe Cirino, David Fulton, Roberto Motterlini. Nitric oxide synthases. Accessed on 23/03/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=253.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.