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J. Biol. Chem., Vol. 280, Issue 27, 25735-25742, July 8, 2005

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Structure and Mechanism of the Alkyl Hydroperoxidase AhpC, a Key Element of the Mycobacterium tuberculosis Defense System against Oxidative Stress^*

Beatriz G. Guimarães, Hélène Souchon, Nadine Honoré¶, Brigitte Saint-Joanis¶, Roland Brosch¶, William Shepard||, Stewart T. Cole¶, and Pedro M. Alzari**

From the Unité de Biochimie Structurale, CNRS URA 2185, 25 rue du Docteur Roux and^¶ Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France and ^||European Synchrotron Radiation Facility, 6 rue Jules Horowitz, 38043 Grenoble Cedex, France

The peroxiredoxin AhpC from Mycobacterium tuberculosis (MtAhpC) is the foremost element of a NADH-dependent peroxidase and peroxynitrite reductase system, where it directly reduces peroxides and peroxynitrite and is in turn reduced by AhpD and other proteins. Overexpression of MtAhpC in isoniazid-resistant strains of M. tuberculosis harboring mutations in the catalase/peroxidase katG gene provides antioxidant protection and may substitute for the lost enzyme activities. We report here the crystal structure of oxidized MtAhpC trapped in an intermediate oligomeric state of its catalytic cycle. The overall structure folds into a ring-shaped hexamer of dimers instead of the usual pentamer of dimers observed in other reduced peroxiredoxins. Although the general structure of the functional dimer is similar to that of other 2-Cys peroxiredoxins, the -helix containing the peroxidatic cysteine Cys⁶¹ undergoes a unique rigid-body movement to allow the formation of the disulfide bridge with the resolving cysteine Cys¹⁷⁴. This conformational rearrangement creates a large internal cavity enclosing the active site, which might be exploited for the design of inhibitors that could block the catalytic cycle. Structural and mutagenesis evidence points to a model for the electron transfer pathway in MtAhpC that accounts for the unusual involvement of three cysteine residues in catalysis and suggests a mechanism by which MtAhpC can specifically interact with different redox partners.

Received for publication, March 21, 2005 , and in revised form, May 2, 2005.

The atomic coordinates and structure factors (code 2BMX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by grants from the Institut Pasteur (GPH-5), the Ministry of Research (Contract 01-B-0095), the European Union (X-TB, Contract QLK2-CT-2001-02018, and SPINE, Contract QLG2-CT-2002-00988), and the National Genopole Network, France (Contract RNG-2002-008). 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.

Recipient of a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Brazil). Present address: Centro de Biologia Molecular Estrutural, Laboratório Nacional de Luz Síncrotron, Caixa Postal 6192, CEP 13084-971, Campinas, Sao Paulo, Brasil.

^** To whom correspondence should be addressed: Unité de Biochimie Structurale, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: 33-145688607; Fax: 33-145688604; E-mail: alzari{at}pasteur.fr.

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