Enzyme Inhibition by Peroxynitrite-Mediated Tyrosine Nitration and Thiol Oxidation

Author(s): Andreas Daiber, Markus Bachschmid

Journal Name: Current Enzyme Inhibition

Volume 3 , Issue 2 , 2007

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Nitric oxide (.NO, EDRF), a potent vasodilator is formed from arginine by NO synthases. Under physiological conditions endothelial NO synthase (NOS3) yields low steady-state .NO levels dilating the smooth muscle of the vasculature via activation of the soluble guanylyl cyclase. Superoxide (O2.-), a toxic reactive oxygen species that easily reacts with metal-sulfur-clusters and causes oxidative damage via Fenton chemistry, is formed by NADPH oxidases, xanthine oxidase, uncoupled NOS3 and mitochondria. Under physiological conditions excessive activation of these sources is suppressed. Accordingly, steady-state levels of O2.- are low. In aging or diseases such as inflammation, hypertension and atherosclerosis O2.- formation increases dramatically and at the same time inducible NO synthase (NOS2) generates high concentrations of .NO. Both radicals react in a diffusion-controlled fashion to yield the toxic and highly reactive nitrogen species peroxynitrite (ONOO-) which has been shown to oxidize all kinds of biomolecules like proteins, DNA, lipids as well as low molecular weight antioxidants. The most prominent protein modifications are the nitration and dimerization of tyrosine residues, the oxidation of cysteine thiol-groups as well as the oxidation of methionine sulfur-groups. Moreover, disruption of metal-sulfur-clusters has been demonstrated to result in oxidative inactivation of enzymatic catalysis. These oxidative modifications by ONOO- may modulate or inhibit enzymatic activity. However, since ONOO- has been shown to contribute to pathophysiological conditions in various cardiovascular, neurodegenerative and inflammatory diseases, the majority of ONOO-- mediated oxidations obviously must have functional consequences that result in interference with cellular redox-signaling, cell damage or in death of the entire organism.

Keywords: Superoxide, nitric oxide, peroxynitrite, tyrosine nitration, thiol oxidation

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Article Details

Year: 2007
Page: [103 - 117]
Pages: 15
DOI: 10.2174/157340807780598369
Price: $65

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