title: Deciphering the genetic bases of the structural diversity of phenolic glycolipids in strains of the Mycobacterium tuberculosis complex.
abstract: 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.
authors.affiliation: 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, Toulouse Cedex 4, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Malaga
authors.forename: Patricia
authors.initials: P
authors.lastname: Constant
authors.forename: Daniel
authors.initials: D
authors.lastname: Euphrasie
authors.forename: Angel
authors.initials: A
authors.lastname: Cataldi
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Reyrat
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D002238:Carbohydrate Epimerases / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D016368:Frameshift Mutation; D005643:Fucose / Q000235:genetics / Q000378:metabolism; D006017:Glycolipids / Q000235:genetics / Q000378:metabolism*; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D009166:Mycobacterium leprae / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D013045:Species Specificity; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D006017:Glycolipids; D037521:Virulence Factors; C045169:phenolic glycolipid I, Mycobacterium leprae; D005643:Fucose; D016695:Glycosyltransferases; C493168:Rv2958c protein, Mycobacterium tuberculosis; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase; D002238:Carbohydrate Epimerases