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J. Biol. Chem., Vol. 279, Issue 41, 42584-42592, October 8, 2004

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Molecular Dissection of the Role of Two Methyltransferases in the Biosynthesis of Phenolglycolipids and Phthiocerol Dimycoserosate in the Mycobacterium tuberculosis Complex^*

Esther Pérez, Patricia Constant, Françoise Laval, Anne Lemassu, Marie-Antoinette Lanéelle, Mamadou Daffé, and Christophe Guilhot¶

From the Département "Mécanismes Moléculaires des Infections Mycobactériennes," Institut de Pharmacologie et Biologie Structurale, CNRS and Université Paul Sabatier (Unité Mixte de Recherche 5089), 205 route de Narbonne, 31077 Toulouse Cedex, France

A few mycobacterial species, most of which are pathogenic for humans, produce dimycocerosates of phthiocerol (DIM) and of glycosylated phenolphthiocerol, also called phenolglycolipid (PGL), two groups of molecules shown to be important virulence factors. The biosynthesis of these molecules is a very complex pathway that involves more than 15 enzymatic steps and has just begun to be elucidated. Most of the genes known to be involved in these pathways are clustered on the chromosome of M. tuberculosis. Based on their amino acid sequences, we hypothesized that the proteins encoded by Rv2952 and Rv2959c, two open reading frames of this locus, are involved in the transfer of methyl groups onto various hydroxyl functions during the biosynthesis of DIM, PGL, and related p-hydroxybenzoic acid derivatives (p-HBAD). Using allelic exchange and site-specific recombination, we produced three recombinant strains of Mycobacterium tuberculosis carrying insertions in Rv2952 or Rv2959c. Analysis of these mutants revealed that (i) the protein encoded by Rv2952 is a methyltransferase catalyzing the transfer of a methyl group onto the lipid moiety of phthiotriol and glycosylated phenolphthiotriol dimycocerosates to form DIM and PGL, respectively, (ii) Rv2959c is part of an operon including the newly characterized Rv2958c gene that encodes a glycosyltransferase also involved in PGL and p-HBAD biosynthesis, and (iii) the enzyme encoded by Rv2959c catalyzes the O-methylation of the hydroxyl group located on carbon 2 of the rhamnosyl residue linked to the phenolic group of PGL and p-HBAD produced by M. tuberculosis. These data further extend our understanding of the biosynthesis of important mycobacterial virulence factors and provide additional tools to decipher the molecular mechanisms of action of these molecules during the pathogenesis of tuberculosis.

Received for publication, June 2, 2004 , and in revised form, July 20, 2004.

^* This work was supported by the CNRS, France. 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 Marie Curie Fellowship from the European Union.

To whom correspondence may be addressed. Tel.: 33-561-175-845; Fax: 33-561-175-994; E-mail: Mamadou.Daffe{at}ipbs.fr. ¶ To whom correspondence may be addressed. Tel.: 33-561-175-845; Fax: 33-561-175-994; Email: Christophe.Guilhot{at}ipbs.fr.

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