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J. Biol. Chem., Vol. 281, Issue 7, 4434-4445, February 17, 2006

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Further Insight into S-Adenosylmethionine-dependent Methyltransferases

STRUCTURAL CHARACTERIZATION OF Hma, AN ENZYME ESSENTIAL FOR THE BIOSYNTHESIS OF OXYGENATED MYCOLIC ACIDS IN MYCOBACTERIUM TUBERCULOSIS^*

Fanny Boissier, Fabienne Bardou, Valérie Guillet, Sandrine Uttenweiler-Joseph^¶, Mamadou Daffé, Annaïk Quémard, and Lionel Mourey¹

From the Départements Mécanismes Moléculaires des Infections Mycobactériennes and ^¶Protéome et Cibles Thérapeutiques and the Plate-Forme Protéomique, Institut de Pharmacologie et de Biologie Structurale du CNRS et de l'Université Paul Sabatier, 31077 Toulouse Cedex 04, France

Mycolic acids are major and specific components of the cell envelope of Mycobacteria that include Mycobacterium tuberculosis, the causative agent of tuberculosis. Their metabolism is the target of the most efficient antitubercular drug currently used in therapy, and the enzymes that are involved in the production of mycolic acids represent important targets for the development of new drugs effective against multidrug-resistant strains. Among these are the S-adenosylmethionine-dependent methyltransferases (SAM-MTs) that catalyze the introduction of key chemical modifications in defined positions of mycolic acids. Some of these subtle structural variations are known to be crucial for both the virulence of the tubercle bacillus and the permeability of the mycobacterial cell envelope. We report here the structural characterization of the enzyme Hma (MmaA4), a SAM-MT that is unique in catalyzing the introduction of a methyl branch together with an adjacent hydroxyl group essential for the formation of both keto- and methoxymycolates in M. tuberculosis. Despite the high propensity of Hma to proteolytic degradation, the enzyme was produced and crystallized, and its three-dimensional structure in the apoform and in complex with S-adenosylmethionine was solved to about 2 Å. Thestructuresshowtheimportantroleplayedbythemodificationsfound within mycolic acid SAM-MTs, especially the2-3 motif and the chemical environment of the active site. Essential information with respect to cofactor and substrate binding, selectivity and specificity, and about the mechanism of catalytic reaction were derived.

Received for publication, September 19, 2005 , and in revised form, November 18, 2005.

^* This work was supported by the CNRS and the Ministère de l'Education Nationale de l'Enseignement Supérieur et de la Recherche (Program Action Concertée Incitative: Molécules et Cibles Thérapeutiques). 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 To whom correspondence should be addressed: IPBS-CNRS (UMR 5089), 205 route de Narbonne, 31077 Toulouse Cedex 04, France. Tel.: 33-561-175-436; Fax: 33-561-175-994; E-mail: lionel.mourey{at}ipbs.fr.

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