HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 19, 14101-14112, May 11, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/19/14101    most recent M609237200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maréchal, A. Articles by Santolini, J. Search for Related Content PubMed PubMed Citation Articles by Maréchal, A. Articles by Santolini, J. Social Bookmarking                      What's this?

Activation of Peroxynitrite by Inducible Nitric-oxide Synthase

A DIRECT SOURCE OF NITRATIVE STRESS^*

Amandine Maréchal, Tony A. Mattioli, Dennis J. Stuehr, and Jérôme Santolini¹

From the Laboratoire de Stress Oxydant et Détoxication, iBiTec-S, Commissariat à l'Energie Atomique, Saclay, Gif-sur-Yvette 91191 Cedex, France and the Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195

In mammals, nitric oxide (NO) is an essential biological mediator that is exclusively synthesized by nitric-oxide synthases (NOSs). However, NOSs are also directly or indirectly responsible for the production of peroxynitrite, a well known cytotoxic agent involved in numerous pathophysiological processes. Peroxynitrite reactivity is extremely intricate and highly depends on activators such as hemoproteins. NOSs present, therefore, the unique ability to both produce and activate peroxynitrite, which confers upon them a major role in the control of peroxynitrite bioactivity. We report here the first kinetic analysis of the interaction between peroxynitrite and the oxygenase domain of inducible NOS (iNOSoxy). iNOSoxy binds peroxynitrite and accelerates its decomposition with a second order rate constant of 22 x 10⁴ M^–1s^–1 at pH 7.4. This reaction is pH-dependent and is abolished by the binding of substrate or product. Peroxynitrite activation is correlated with the observation of a new iNOS heme intermediate with specific absorption at 445 nm. iNOSoxy modifies peroxynitrite reactivity and directs it toward one-electron processes such as nitration or one-electron oxidation. Taken together our results suggest that, upon binding to iNOSoxy, peroxynitrite undergoes homolytic cleavage with build-up of an oxo-ferryl intermediate and concomitant release of a radical. Successive cycles of peroxynitrite activation were shown to lead to iNOSoxy autocatalytic nitration and inhibition. The balance between peroxynitrite activation and self-inhibition of iNOSoxy may determine the contribution of NOSs to cellular oxidative stress.

Received for publication, September 29, 2006 , and in revised form, March 16, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text with equations and reactions, as well as Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 33-1-690-85-363; Fax: 33-1-690-88-717; E-mail: jerome.santolini{at}cea.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. M. Vaz and O. Augusto Reactive Oxygen Species Special Feature: Inhibition of myeloperoxidase-mediated protein nitration by tempol: Kinetics, mechanism, and implications PNAS, June 17, 2008; 105(24): 8191 - 8196. [Abstract] [Full Text] [PDF]