Nitric oxide synthases: catalytic function and progress towards selective inhibition

Abstract

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.