Nitric Oxide Synthase and Oxidative Stress: Regulation of Nitric Oxide Synthase

Abstract

Nitric oxide has been found to play an important role as a signal molecule in many parts of the organism as well as a cytotocic effector molecule of nonspecific immune response. Nitric oxide is very important functions both in helminthes and mammalian hosts. Nitric oxide may react with proteins and nucleic acids. In addition to binding to heme groups, e.g. of guanylate cyclase, hemoglobin, and cytochrome C oxidase, NO may react with nucleophilic centers like sulfur, nitrogen, oxygen and aromatic carbons. The prime target for covalent binding of NO to a functional groups in proteins under physiological condition in the presence of oxygen are SH groups. The intra-mitochondrial reaction of NO with superoxide anion yields peroxynitrite, which irreversibly modifies susceptible targets within the mitochondria, inducing oxidative and/or nitrative stresses. The signal molecule of NO is synthesized by constitutive nitric oxide synthase (cNOS). The killer molecule NO is synthesized by inducible NOS (iNOS). There is no signal or killer NO – it depends on the environments and partners involved – be very careful in that. Yes, the production is regulated in different ways. Inducible NOS is induced by numerous inflammatory stimuli, including endotoxin, cytokines and excretory/secretory products (ESP) of helminthes. ESP directly interact with the immune system and modulate host immunity. Nitric oxide is a highly reactive and unstable free radical gas that is produced by oxidation of Larginine by oxygen and NADPH as electron donor to citrulline mediated by a family of homodimer named nitric oxide synthase. In addition to Larginine-NO pathway, L-arginine is also metabolized to L-ornithine and urea by arginase enzyme. A side from blocking NO synthesis by depleting the cell of substrate for NOS, the arginase-mediated removal of Larginine inhibits the expression of inducible NOS (iNOS) by repressing the translation as well as the stability of iNOS protein. Furthermore, arginase may inhibit iNOS-mediated NO production through the generation of urea.