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.

Anti-Inflammatory Effects of 6,8-Diprenyl-7,4′-dihydroxyflavanone from Sophora tonkinensis on Lipopolysaccharide-Stimulated RAW 264.7 Cells

“…Overproduction of NO appears to be connected to tissue damage and organ dysfunction [27]. In the present study, we demonstrated that DDF inhibited LPS-stimulated NO production in RAW 264.7 cells.…”

Nitric Oxide Synthase Inhibitors

“…The compounds were isothiourea derivatives (Figure 3-1) designed as l-arginine-competitive reversible inhibitors of human iNOS, with a K i = 47 nM and a 190-fold selectivity over eNOS but only ~5-fold over nNOS [10,20]. Further studies of the group led to the design of compound 1400W (Figure 3), which is highly selective over eNOS and nNOS and able to penetrate into cells and tissues [10,21].…”

“…This ligand-receptor interaction profile is similar to all isoforms, which generates a challenge to selectivity [11]. [10].…”

Assessing Nitric Oxide (NO) in Higher Plants: An Outline

“…However, two scientific reports published in 1987 by two independent groups demonstrated that NO, previously designated as endothelium-derived relaxing factor (EDRF), was involved in the regulation of vasodilation of the blood vessels [3,4]. Then, it was shown that this molecule was generated in mammalian cells from the amino acid L-arginine by a family of enzymes designated as nitric oxide synthases (NOSs) [5]. Later, it was revealed that NO is also involved in both nervous and immune systems in animal organisms.…”