Biogenesis of lipoarabinomannan in mycobacteria Summary Phosphatidylinositol mannosides (PIM) and their multiglycosylated counterparts, lipomannan (LM) and lipoarabinomannan (LAM) are complex glycolipids and lipoglycans found in the envelopes of all mycobacterial species. They play various essential although poorly defined roles in mycobacterial physiology and are important immunomodulatory molecules in the course of tuberculosis and leprosy as well as key ligands promoting the entry of mycobacteria into phagocytic and non-phagocytic cells. Although much progress has been made over the last 20 years in elucidating the structures of these molecules, knowledge of the pathways leading to their biosynthesis, assembling and transport to the cell surface is still incomplete. The elucidation of these pathways, in addition to providing fundamental knowledge about the biochemistry of Mycobacterium tuberculosis, is expected to lead to the discovery of essential enzymes and transporters that could represent interesting targets for novel anti-TB drugs. The availability of recombinant mycobacterial strains accumulating biosynthetic precursors of these molecules would facilitate structure-function relationship studies and that of defined M. tuberculosis mutants deficient in various aspects of PIM, LM and LAM synthesis would allow a precise assessment of the contribution of these molecules to the immunopathogenesis of tuberculosis in vivo. Following an integrated approach in the form of bioinformatics, genetics and biochemistry, we propose to pursue our work on the identification and functional characterization of the enzymes involved in the elongation and assembling of PIM, LM and LAM and to further extend this work to the characterization of the transporters responsible for the translocation of biosynthetic intermediates and end products across the different layers of the cell envelope. Abbreviations: AM, arabinomannan;AcylT, acyltransferase;Araf, arabinofuranosyl;AraT, arabinosyltransferase;CZE, capillary zone electrophoresis;DOC, deoxycholate;ESI, electrospray ionization;GT, glycosyltransferase;LAM, lipoarabinomannan;LM, lipomannan;MALDI-TOF, Matrix-Assisted Laser desorption/ionization time of flight;Manp, mannopyranosyl;ManT, mannosyltransferase;MPI, mannosylated phosphatidylinositol;MS, mass spectrometry;myo-Ins, myo-inositol;ORF, open reading frame;investigator, phosphatidyl-myo-inositol;PIM, phosphatidyl-myo-inositol mannosides;TFA, trifluoroacetic acid;TLC, thin-layer chromatography. Nomenclature: PIM is used to describe the global family of phosphatidylinositol mannosides that carries one to four fatty acids (attached to the glycerol, inositol and/or mannose) and one to six mannose residues. In AcXPIMY, x refers to the number of acyl groups esterified to available hydroxyls on the mannose or myo-inositol residues, y refers to the number of mannose residues;e.g. Ac1PIM1 corresponds to the phosphatidylinositol mono-mannoside PIM1 carrying two acyl groups attached to the glycerol (the diacylglycerol substituent) and one acyl group esterified to the mannose residue.
Dissection of the PIM, LM and LAM pathways in Mycobacterium tuberculosis will lead to the discovery of novel classes of essential enzymes and transporters that may represent attractive targets for therapeutic intervention. In addition, the mutants defective in some aspects of PIM, LM or LAM synthesis will help define the precise role of these molecules in immunopathogenesis.
|Decout, Alexiane; Silva-Gomes, Sandro; Drocourt, Daniel et al. (2018) Deciphering the molecular basis of mycobacteria and lipoglycan recognition by the C-type lectin Dectin-2. Sci Rep 8:16840|
|Angala, Shiva K; Pal?eková, Zuzana; Belardinelli, Juan M et al. (2018) Covalent modifications of polysaccharides in mycobacteria. Nat Chem Biol 14:193-198|
|Belardinelli, Juan Manuel; Jackson, Mary (2017) Green Fluorescent Protein as a protein localization and topological reporter in mycobacteria. Tuberculosis (Edinb) 105:13-17|
|Angala, Shiva Kumar; McNeil, Michael R; Shi, Libin et al. (2017) Biosynthesis of the Methylthioxylose Capping Motif of Lipoarabinomannan in Mycobacterium tuberculosis. ACS Chem Biol 12:682-691|
|Albesa-Jové, David; Svetlíková, Zuzana; Tersa, Montse et al. (2016) Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA. Nat Commun 7:10906|
|Angala, Shiva Kumar; McNeil, Michael R; Zou, Lu et al. (2016) Identification of a Novel Mycobacterial Arabinosyltransferase Activity Which Adds an Arabinosyl Residue to ?-d-Mannosyl Residues. ACS Chem Biol 11:1518-24|
|Larrouy-Maumus, Gérald; Gilleron, Martine; Skovierová, Henrieta et al. (2015) A glycomic approach reveals a new mycobacterial polysaccharide. Glycobiology 25:1163-71|
|Wheat, William H; Dhouib, Rabeb; Angala, Shiva K et al. (2015) The presence of a galactosamine substituent on the arabinogalactan of Mycobacterium tuberculosis abrogates full maturation of human peripheral blood monocyte-derived dendritic cells and increases secretion of IL-10. Tuberculosis (Edinb) 95:476-89|
|Svetlíková, Zuzana; Baráth, Peter; Jackson, Mary et al. (2014) Purification and characterization of the acyltransferase involved in biosynthesis of the major mycobacterial cell envelope glycolipid--monoacylated phosphatidylinositol dimannoside. Protein Expr Purif 100:33-9|
|Albesa-Jové, David; Giganti, David; Jackson, Mary et al. (2014) Structure-function relationships of membrane-associated GT-B glycosyltransferases. Glycobiology 24:108-24|
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