Publications

• Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum.

  Vergnolle O., Chavadi S.S., Edupuganti U.R., Mohandas P., Chan C., Zeng J., Kopylov M., Angelo N.G., Warren J.D., Soll C.E., Quadri L.E.

  Phenolic glycolipids (PGLs) are polyketide synthase-derived glycolipids unique to pathogenic mycobacteria. PGLs are found in several clinically relevant species, including various Mycobacterium tuberculosis strains, Mycobacterium leprae, and several nontuberculous mycobacterial pathogens, such as ... >> More

  Phenolic glycolipids (PGLs) are polyketide synthase-derived glycolipids unique to pathogenic mycobacteria. PGLs are found in several clinically relevant species, including various Mycobacterium tuberculosis strains, Mycobacterium leprae, and several nontuberculous mycobacterial pathogens, such as M. marinum. Multiple lines of investigation implicate PGLs in virulence, thus underscoring the relevance of a deep understanding of PGL biosynthesis. We report mutational and biochemical studies that interrogate the mechanism by which PGL biosynthetic intermediates (p-hydroxyphenylalkanoates) synthesized by the iterative polyketide synthase Pks15/1 are transferred to the noniterative polyketide synthase PpsA for acyl chain extension in M. marinum. Our findings support a model in which the transfer of the intermediates is dependent on a p-hydroxyphenylalkanoyl-AMP ligase (FadD29) acting as an intermediary between the iterative and the noniterative synthase systems. Our results also establish the p-hydroxyphenylalkanoate extension ability of PpsA, the first-acting enzyme of a multisubunit noniterative polyketide synthase system. Notably, this noniterative system is also loaded with fatty acids by a specific fatty acyl-AMP ligase (FadD26) for biosynthesis of phthiocerol dimycocerosates (PDIMs), which are nonglycosylated lipids structurally related to PGLs. To our knowledge, the partially overlapping PGL and PDIM biosynthetic pathways provide the first example of two distinct, pathway-dedicated acyl-AMP ligases loading the same type I polyketide synthase system with two alternate starter units to produce two structurally different families of metabolites. The studies reported here advance our understanding of the biosynthesis of an important group of mycobacterial glycolipids. << Less

  J. Bacteriol. 197:1040-1050(2015) [PubMed] [EuropePMC]

  This publication is cited by 19 other entries.

• Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis.

  Simeone R., Leger M., Constant P., Malaga W., Marrakchi H., Daffe M., Guilhot C., Chalut C.

  Phthiocerol and phthiodiolone dimycocerosates (DIMs) and phenolic glycolipids (PGLs) are complex lipids located at the cell surface of Mycobacterium tuberculosis that play a key role in the pathogenicity of tuberculosis. Most of the genes involved in the biosynthesis of these compounds are cluster ... >> More

  Phthiocerol and phthiodiolone dimycocerosates (DIMs) and phenolic glycolipids (PGLs) are complex lipids located at the cell surface of Mycobacterium tuberculosis that play a key role in the pathogenicity of tuberculosis. Most of the genes involved in the biosynthesis of these compounds are clustered on a region of the M. tuberculosis chromosome, the so-called DIM + PGL locus. Among these genes, four ORFs encode FadD proteins, which activate and transfer biosynthetic intermediates onto various polyketide synthases that catalyze the formation of these lipids. In this study, we investigated the roles of FadD22, FadD26 and FadD29 in the biosynthesis of DIMs and related compounds. Biochemical characterization of the lipids produced by a spontaneous Mycobacterium bovis BCG mutant harboring a large deletion within fadD26 revealed that FadD26 is required for the production of DIMs but not of PGLs. Additionally, using allelic exchange recombination, we generated an unmarked M. tuberculosis mutant containing a deletion within fadD29. Biochemical analyses of this strain revealed that, like fadD22, this gene encodes a protein that is specifically involved in the biosynthesis of PGLs, indicating that both FadD22 and FadD29 are responsible for one particular reaction in the PGL biosynthetic pathway. These findings were also supported by in vitro enzymatic studies showing that these enzymes have different properties, FadD22 displaying a p-hydroxybenzoyl-AMP ligase activity, and FadD29 a fatty acyl-AMP ligase activity. Altogether, these data allowed us to precisely define the functions fulfilled by the various FadD proteins encoded by the DIM + PGL cluster. << Less

  FEBS J. 277:2715-2725(2010) [PubMed] [EuropePMC]

  This publication is cited by 19 other entries.