Nitric oxide synthases: structure, function and inhibition

Abstract

This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3

“…9). Therefore, we decided to examine the gene expression levels of a few genes known to be involved in ROS production including NOX1, NOX4 (NADPH oxidases, involved in production of Oxygen radicals 25 ), NOXA1 (NOX-activating protein 26 ) and NOS2 (nitric oxide synthase, involved in the formation of free radicals 27 ).…”

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

“…The KCl pre-contracted and cocktail-treated arterial mesenteric vasculatures of control, eNOS or iNOS KO mice were perfused with vehicle or 7-nitroindazole (7-NI) (100 mmol l À1 , for 15 min prior to and during the entire experiments) (Alderton et al, 2001;Ralevic, 2002) to evaluate the implication of neuronal NOS in the reduction in perfusion pressure afforded by PNS. Dose-dependent responses to haCGRP administered as a bolus (in 1 ml) were also assessed in the arterial mesenteric vasculature of control or endothelial NOS knockout mice as well as in 7-NI pretreated vascular circuits derived from wild-type animals.…”

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

“…High amounts of NO are produced through the inducible nitric oxide synthase (iNOS) pathway in response to proinflammatory cytokines and bacterial products. Expression of iNOS has been shown to be regulated both at transcriptional and post-translational levels in activated macrophages, but many of the mechanisms are still unknown (MacMicking et al, 1997;Alderton et al, 2001;Kleinert et al, 2003;Aktan, 2004;Korhonen et al, 2005).…”