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J. Biol. Chem., Vol. 278, Issue 46, 45352-45357, November 14, 2003

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Kinetic Characterization of the Chemical Steps Involved in the Catalytic Mechanism of Methionine Sulfoxide Reductase A from Neisseria meningitidis^*

Mathias Antoine, Sandrine Boschi-Muller, and Guy Branlant

From the UMR 7567 CNRS/UHP – Maturation des ARN et Enzymologie Moléculaire, Faculté des Sciences, Bld des Aiguillettes, BP 239, 54506 Vandoeuvre-les-Nancy, France

Oxidation of methionine into methionine sulfoxide is associated with many pathologies and is described to exert regulatory effects on protein functions. Two classes of methionine sulfoxide reductases, called MsrA and MsrB, have been described to reduce the S and the R isomers of the sulfoxide of methionine sulfoxide back to methionine, respectively. Although MsrAs and MsrBs display quite different x-ray structures, they share a similar, new catalytic mechanism that proceeds via the sulfenic acid chemistry and that includes at least three chemical steps with 1) the formation of a sulfenic acid intermediate and the concomitant release of methionine; 2) the formation of an intra-disulfide bond; and 3) the reduction of the disulfide bond by thioredoxin. In the present study, it is shown that for the Neisseria meningitidis MsrA, 1) the rate-limiting step is associated with the reduction of the Cys-51/Cys-198 disulfide MsrA bond by thioredoxin; 2) the formation of the sulfenic acid intermediate is very efficient, thus suggesting catalytic assistance via amino acids of the active site; 3) the rate-determining step in the formation of the Cys-51/Cys-198 disulfide bond is that leading to the formation of the sulfenic intermediate on Cys-51; and 4) the apparent affinity constant for methionine sulfoxide in the methionine sulfoxide reductase step is 80-fold higher than the K_m value determined under steady-state conditions.

Received for publication, July 11, 2003 , and in revised form, September 2, 2003.

^* This research was supported by the Centre National de la Recherche Scientifique ("Programme Physique et Chimie du Vivant 2000," "Programme Protéomique et Génie des Protéines 2001"), the University Henry Poincaré Nancy I, the Association pour la Recherche sur le Cancer (Association pour la Recherche sur le Cancer Grant 5436), and the Institut Fédératif de Recherches 111 Bioingénierie. 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.

To whom correspondence should be addressed. Tel.: 33-3-83-68-43-04; Fax: 33-3-83-68-43-07; E-mail: guy.branlant{at}maem.uhp-nancy.fr.

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