tailieunhanh - Báo cáo khoa học: Molecular dissection of the biosynthetic relationship between phthiocerol and phthiodiolone dimycocerosates and their critical role in the virulence and permeability of Mycobacterium tuberculosis

Phthiocerol dimycocerosates and related compounds are important mole-cules in the biology of Mycobacterium tuberculosis, playing a key role in the permeability barrier and in pathogenicity. Both phthiocerol dimyco-cerosates, the major compounds, and phthiodiolone dimycocerosates, the minor constituents, are found in the cell envelope ofM. tuberculosis, but their specific roles in the biology of the tubercle bacillus have not been established yet. | ỊFEBS Journal Molecular dissection of the biosynthetic relationship between phthiocerol and phthiodiolone dimycocerosates and their critical role in the virulence and permeability of Mycobacterium tuberculosis Roxane Simeone Patricia Constant Wladimir Malaga Christophe Guilhot Mamadou Daffe and Christian Chalut Departement Mecanismes Moleculaires des Infections Mycobacteriennes Institut de Pharmacologie et de Biologie Structurale Toulouse France Keywords ketoreductase Mycobacterium tuberculosis phenolic glycolipids phthiocerol dimycocerosates tuberculosis Correspondence C. Chalut Institut de Pharmacologie et de Biologie Structurale 205 route de Narbonne 31077 Toulouse Cedex France Fax 33 5 6117 5994 Tel 33 5 6117 5473 E-mail Received 12 January 2007 revised 9 February 2007 accepted 14 February 2007 doi Phthiocerol dimycocerosates and related compounds are important molecules in the biology of Mycobacterium tuberculosis playing a key role in the permeability barrier and in pathogenicity. Both phthiocerol dimyco-cerosates the major compounds and phthiodiolone dimycocerosates the minor constituents are found in the cell envelope of M. tuberculosis but their specific roles in the biology of the tubercle bacillus have not been established yet. According to the current model of their biosynthesis phthiocerol is produced from phthiodiolone through a two-step process in which the keto group is first reduced and then methylated. We have previously identified the methyltransferase enzyme that is involved in this process encoded by the gene Rv2952 in M. tuberculosis. In this study we report the construction and biochemical analyses of an M. tuberculosis strain mutated in gene Rv2951c. This mutation prevents the formation of phthiocerol and phenolphthiocerol derivatives but leads to the accumulation of phthiodiolone dimycocerosates and glycosylated phenolphthiodio-lone dimycocerosates. These results provide the formal .