Nitric Oxide Synthase

Nitric Oxide Synthase

Nitric oxide synthases (EC 1.14.13.39) (NOSs) are a family of enzymes that catalyze the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes. It is the intercellular signal that controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis (growth of new blood vessels) and in the development of nervous system. It is believed to function as a retrograde neurotransmitter and hence is likely to be important in learning. Nitric oxide signalling is mediated in mammals by the calcium/calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS (neuronal NOS); the inducible isoform iNOS is involved in immune response, binds calmodulin at all physiologically relevant concentrations, and produces large amounts of NO as a defense mechanism. It is the proximate cause of septic shock and may play a role in many diseases with an autoimmune etiology.

The canonical reaction catalyzed by NOS is:

• L-arginine + 3/2 NADPH + H+ + 2 O₂ = citrulline + nitric oxide + 3/2 NADP+

NOS isoforms catalyze many other leak and side reactions such as superoxide production at the expense of NADPH, so this stoichiometry is not generally observed. The unusual stoichiometry reflects the three electrons supplied per NO by NADPH; NO is a free radical with an unpaired electron.

NOSs are unusual in that they require five cofactors. Eukaryotic NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: NADPH --> FAD --> FMN --> heme --> O₂. Tetrahydrobiopterin provides an additional electron during the catalytic cycle which is replaced during turnover. ). NOS is the only known enzyme that binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, tetrahydrobiopterin (BH₄) and calmodulin.