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J. Biol. Chem., Vol. 283, Issue 22, 15177-15184, May 30, 2008

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Deciphering the Genetic Bases of the Structural Diversity of Phenolic Glycolipids in Strains of the Mycobacterium tuberculosis Complex^*

Wladimir Malaga, Patricia Constant, Daniel Euphrasie, Angel Cataldi^¶, Mamadou Daffé, Jean-Marc Reyrat, and Christophe Guilhot¹

From the Université Paul Sabatier and CNRS, Institut de Pharmacologie et Biologie Structurale (Unité Mixte de Recherche 5089), Département "Mécanismes Moléculaires des Infections Mycobactériennes," 205 Route de Narbonne, 31077 Toulouse Cedex 4, France, Université Paris Descartes, Faculté de Médecine René Descartes, Inserm U570, Unité de Pathogénie des Infections Systémiques, 75730 Paris Cedex 15, France, and ^¶Institute of Biotechnology, CNIA-INTA, 1712 Castelar, Argentina

Phenolic glycolipids (PGL) play a major role in the virulence of mycobacteria, notably in strains of the Mycobacterium tuberculosis complex and in Mycobacterium leprae. The structure of the carbohydrate domain of these compounds is highly variable, and the genetic bases for these variations remain unknown. We demonstrated that the monoglycosylated PGL formed by Mycobacterium bovis differs from the triglycosylated PGL synthesized by M. tuberculosis (PGL-tb) because of the following two genetic defects: a frameshift mutation within the gene Rv2958c, encoding a glycosyltransferase involved in the transfer of the second rhamnosyl residue of the PGL-tb, and a deletion of a region that encompasses two genes, which encode a GDP-D-mannose 4,6-dehydratase and a GDP-4-keto-6-deoxy-D-mannose-3,5-epimerase/reductase, required for the formation of activated L-fucose. Expression of these three genes in M. bovis BCG allowed synthesis of PGL-tb in this recombinant strain. Additionally, we showed that all M. bovis, Mycobacterium microti, Mycobacterium pinnipedii, and some Mycobacterium africanum strains harbor the same frameshift mutation in their Rv2958c orthologs. Consistently, the structure of PGLs purified from M. africanum (harboring the Rv2958c mutation) and M. pinnipedii strains revealed that these compounds are monoglycosylated PGL. These findings explain the specificity of PGL-tb production by some strains of the M. tuberculosis complex and have important implications for our understanding of the evolution of this complex.

Received for publication, December 18, 2007 , and in revised form, April 3, 2008.

^* This work was supported by the Agence Nationale de la Recherche Grant ANR-06-MIME-032. 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: Université Paul Sabatier and CNRS, Institut de Pharmacologie et Biologie Structurale (Unité Mixte de Recherche 5089), Dépt. "Mécanismes Moléculaires des Infections Mycobactériennes," 205 Route de Narbonne, 31077 Toulouse Cedex 4, France. Tel.: 33-561-175 845; Fax: 33-561-175 994; E-mail: Christophe.Guilhot{at}ipbs.fr.

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