Nitric oxide synthases: biochemical and molecular regulation.

Abstract

Nitric oxide synthases are a family of complex cytochrome P450-like hemeproteins that catalyze the five-electron oxidation of L-arginine to form nitric oxide. Nitric oxide synthase apoenzyme is dependent on molecular oxygen, nicotinamide adenine dinucleotide phosphate hydrogen, flavins and tetrahydrobiopterin, and it functions as a dimer. Three human nitric oxide synthase isoforms have been identified to date. The endothelial constitutive, neuronal, and inducible nitric oxide synthase isoforms are found on human chromosomes 7, 12 and 17, respectively. Characterization of the structural organization of the human nitric oxide synthase genes reveals that, although they are structurally related, the mechanisms by which they are regulated are distinct. Expression of the mRNA for endothelial constitutive nitric oxide synthase is regulated at the level of transcription and mRNA stability. The mRNA transcripts derived from the neuronal nitric oxide synthase gene are characterized by a remarkable degree of structural diversity. Levels of inducible nitric oxide synthase mRNA are controlled by interacting combinations of cytokines and biological mediators at the level of gene transcription and mRNA stability.