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J. Biol. Chem., Vol. 279, Issue 41, 42574-42583, October 8, 2004

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Characterization of Three Glycosyltransferases Involved in the Biosynthesis of the Phenolic Glycolipid Antigens from the Mycobacterium tuberculosis Complex^*

Esther Pérez, Patricia Constant, Anne Lemassu, Françoise Laval, 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

Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans, produce highly specific long chain -diols, the dimycocerosates of phthiocerol, and structurally related phenolic glycolipid (PGL) antigens, which are important virulence factors. In addition, M. tuberculosis also secretes glycosylated p-hydroxybenzoic acid methyl esters (p-HBAD) that contain the same carbohydrate moiety as the species-specific PGL of M. tuberculosis (PGL-tb). The genes involved in the biosynthesis of these compounds in M. tuberculosis are grouped on a 70-kilobase chromosomal fragment containing three genes encoding putative glycosyltransferases: Rv2957, Rv2958c, and Rv2962c. To determine the functions of these genes, three recombinant M. tuberculosis strains, in which these genes were individually inactivated, were constructed and biochemically characterized. Our results demonstrated that (i) the biosynthesis of PGL-tb and p-HBAD involves common enzymatic steps, (ii) the Rv2957, Rv2958c, and Rv2962c genes are involved in the formation of the glycosyl moiety of the two classes of molecules, and (iii) the product of Rv2962c catalyzes the transfer of a rhamnosyl residue onto p-hydroxybenzoic acid ethyl ester or phenolphthiocerol dimycocerosates, whereas the products of Rv2958c and Rv2957 add a second rhamnosyl unit and a fucosyl residue to form the species-specific triglycosyl appendage of PGL-tb and p-HBAD. The recombinant strains produced provide the tools to study the role of the carbohydrate domain of PGL-tb and p-HBAD in M. tuberculosis pathogenesis.

Received for publication, June 4, 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; 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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