Nitric oxide synthases: catalytic function and progress towards selective inhibition.
Biosynthesis of nitric oxide (NO) is performed by the dimeric, heme-containing enzyme nitric oxide synthase, which requires the flavins FAD and FMN, as well as the pteridine cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (H4biopterin) in order to catalyze the NADPH-dependent oxidation of L-arginine. The three major isoforms of nitric oxide synthase (NOS), although identical in that they contain a carboxy-terminal reductase and an amino-terminal oxygenase domain, fulfill diverse physiological functions, according to their differing expression patterns and mechanisms of activation. The pteridine H4biopterin, which affects both the conformational stability and activity of NOS, demonstrates anticooperative binding which results in the stoichiometric production of NO and O2-. Physiological mechanisms involving superoxide dismutase and reduced glutathione exist to avoid the subsequent formation of the potent oxidant peroxynitrite. With regard to inhibition of NO production, novel isoform-selective inhibitors are proving useful not only for dissecting the physiological functions of NOS, but also in the development of novel therapeutic agents.
Mayer
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B
Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Austria.
Andrew
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P
D000818:Animals; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D013481:Superoxides; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II