Nitric Oxide Synthases: Gene Structure and Regulation

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The nitric oxide (NO) synthases (NOSs) are a family of complex enzymes that catalyze the five-electron oxidation of L-arginine to form NO and L-citrulline. They are best characterized as cytochrome P-450-like hemeproteins that depend on molecular oxygen, nicotinamide adenine dinucleotide-phosphate (NADPH), flavins, and tetrahydrobiopterin. The NOSs constitute a family with at least three distinct isoforms. In order of their molecular characterization, these include the neuronal (nNOS, NOS1), inducible (iNOS, NOS2), and endothelial constitutive (ecNOS, NOS3) NOSs. Till date, three distinct genes encoding the family of human NOS proteins have been identified and characterized. Analysis of these complex loci reveals that the mechanisms implicated in controlling mRNA expression and structure are unique for the different NOS isoforms. The human nNOS, iNOS, and ecNOS genes are not clustered in the genome, but, rather, are present on human chromosomes 12, 17, and 7, respectively. Detailed analysis of the genomic organization and exodintron structure, including exon sizes and the locations of intronic splice junctions, indicates a remarkably high degree of relatedness among the three genes. This is especially evident upon comparison of the calcium/calmodulin-dependent nNOS and ecNOS. The high degree of conservation among the various NOS isoforms may reflect gene duplication and chromosome transposition events. The only related gene in the human genome is cytochrome P-450 reductase. Regulation of NO synthesis and release occurs at the levels of enzyme activity and mRNA synthesis. The nNOS mRNA is structurally diverse as a consequence of alternative promoters and alternate splicing. The iNOS gene is predominantly regulated at the level of transcription by synergistic combinations of proinflammatory cytokines and bacterial wall products. Changes in mRNA levels of the ecNOS following endothelium activation are mediated by altered rates of transcription as well as by the intriguing process of changes in mRNA stability.

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