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J. Biol. Chem., Vol. 282, Issue 44, 32397-32405, November 2, 2007

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Characterization of the Amino Acids from Neisseria meningitidis Methionine Sulfoxide Reductase B Involved in the Chemical Catalysis and Substrate Specificity of the Reductase Step^*

From the Maturation des ARN et Enzymologie Moléculaire, Unité Mixte de Recherche CNRS-UHP 7567, Nancy Université, Faculté des Sciences et Techniques, Boulevard des Aiguillettes, BP 239, 54506 Vandoeuvre-les-Nancy, France

Methionine sulfoxide reductases (Msrs) are antioxidant repair enzymes that catalyze the thioredoxin-dependent reduction of methionine sulfoxide back to methionine. The Msr family is composed of two structurally unrelated classes of enzymes named MsrA and MsrB, which display opposite stereoselectivities toward the S and R isomers of the sulfoxide function, respectively. Both classes of Msr share a similar three-step chemical mechanism involving first a reductase step that leads to the formation of a sulfenic acid intermediate. In this study, the invariant amino acids of Neisseria meningitidis MsrB involved in the reductase step catalysis and in substrate binding have been characterized by the structure-function relationship approach. Altogether the results show the following: 1) formation of the MsrB-substrate complex leads to an activation of the catalytic Cys-117 characterized by a decreased pK_app of 2.7 pH units; 2) the catalytic active MsrB form is the Cys-117^-/His-103⁺ species with a pK_app of 6.6 and 8.3, respectively; 3) His-103 and to a lesser extent His-100, Asn-119, and Thr-26 (via a water molecule) participate in the stabilization of the polarized form of the sulfoxide function and of the transition state; and 4) Trp-65 is essential for the catalytic efficiency of the reductase step by optimizing the position of the substrate in the active site. A scenario for the reductase step is proposed and discussed in comparison with that of MsrA.

Received for publication, June 8, 2007 , and in revised form, August 23, 2007.

^* This work was supported in part by the CNRS, the University of Nancy I, the Institut Fédératif de Recherche 111 Bioingénierie, the Association pour la Recherche sur le Cancer Grant ARC 5436, and the French Ministry of Research Grants ACI BCMS047 and ACI IMPBio SIRE. 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.

¹ Supported by the French Ministry of Research.

² Supported by the University of Nancy I and the Region Lorraine.

³ To whom correspondence should be addressed: Maturation des ARN et Enzymologie Moléculaire, UMR CNRS-UHP 7567, Nancy Universités, Faculté des Sciences et Techniques, Blvd. des Aiguillettes, BP 239, 54506 Vandoeuvre-les-Nancy, France. 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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