Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier

• Published in: The Journal of biological chemistry Vol. 276; no. 23; pp. 19845 - 19854
• Main Authors: Camacho, L R, Constant, P, Raynaud, C, Laneelle, M A, Triccas, J A, Gicquel, B, Daffe, M, Guilhot, C
• Format: Journal Article
• Language: English
• Published: United States 08.06.2001
• Subjects: Base Sequence; Cell Membrane Permeability; Cell Wall - metabolism; DNA Primers; drrC gene; fadD26 gene; fadD28 gene; Lipids - chemistry; Lipids - genetics; Lipids - physiology; mmpL7 gene; Molecular Structure; Mutagenesis, Insertional; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - metabolism; phthiocerol dimycocerosate; Reverse Transcriptase Polymerase Chain Reaction; Spectrum Analysis
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M100662200

Among the few characterized genes that have products involved in the pathogenicity of Mycobacterium tuberculosis, the etiological agent of tuberculosis, are those of the phthiocerol dimycocerosate (DIM) locus. Genes involved in biosynthesis of these compounds are grouped on a 50-kilobase fragment of the chromosome containing 13 genes. Analysis of mRNA produced from this 50-kilobase fragment in the wild type strain showed that this region is subdivided into three transcriptional units. Biochemical characterization of five mutants with transposon insertions in this region demonstrated that (i) the complete DIM molecules are synthesized in the cytoplasm of M. tuberculosis before being translocated into the cell wall; (ii) the genes fadD26 and fadD28 are directly involved in their biosynthesis; and (iii) both the drrC and mmpL7 genes are necessary for the proper localization of DIMs. Insertional mutants unable to synthesize or translocate DIMs exhibit higher cell wall permeability and are more sensitive to detergent than the wild type strain, indicating for the first time that, in addition to being important virulence factors, extractable lipids of M. tuberculosis play a role in the cell envelope architecture and permeability. This function may represent one of the molecular mechanisms by which DIMs are involved in the virulence of M. tuberculosis.