Molecular Basis of Phosphatidyl-myo-inositol Mannoside Biosynthesis and Regulation in Mycobacteria

ArticleinJournal of Biological Chemistry 285(44):33577-83 · October 2010with9 Reads
DOI: 10.1074/jbc.R110.168328 · Source: PubMed
Abstract
Phosphatidyl-myo-inositol mannosides (PIMs) are unique glycolipids found in abundant quantities in the inner and outer membranes of the cell envelope of all Mycobacterium species. They are based on a phosphatidyl-myo-inositol lipid anchor carrying one to six mannose residues and up to four acyl chains. PIMs are considered not only essential structural components of the cell envelope but also the structural basis of the lipoglycans (lipomannan and lipoarabinomannan), all important molecules implicated in host-pathogen interactions in the course of tuberculosis and leprosy. Although the chemical structure of PIMs is now well established, knowledge of the enzymes and sequential events leading to their biosynthesis and regulation is still incomplete. Recent advances in the identification of key proteins involved in PIM biogenesis and the determination of the three-dimensional structures of the essential phosphatidyl-myo-inositol mannosyltransferase PimA and the lipoprotein LpqW have led to important insights into the molecular basis of this pathway.
    • "Several reports indicate that nucleotide sugar binding triggers and inter-domain rearrangement that brings both domains in close proximity, allowing the generation of a competent active site, including GS, 8-O-tetrangulol bolivosyltransferase LanGT2, and protein O-fucosyltransferase 2 (POFUT2) [49 ,50–53] (Figure 1b ,c). The phosphatidylinositol mannosyltransferase PimA is a membrane-associated enzyme that initiates the biosynthesis of key mycobacterial glycolipids such as phospha- tidylinositol mannosides, lipomannan and lipoarabinomannan (LAM) [54]. The enzyme transfers a Man residue from GDP-Man to the 2 position of the inositol ring of phosphatidylinositol at the inner side of the plasma membrane. "
    [Show abstract] [Hide abstract] ABSTRACT: Glycosyltransferases (GTs) catalyze the transfer of a sugar moiety from nucleotide-sugar or lipid-phospho-sugar donors to a broad range of acceptor substrates, generating a significant amount of structural diversity in biological systems. GTs are highly selective in nature, allowing the recognition of subtle structural differences in the sequences and stereochemistry of their sugar and acceptor substrates. To achieve the enzyme-transition state complex, a particular spatial arrangement of the active site is required, highlighting the importance of protein dynamics, conformational changes and plasticity of GTs during substrate recognition and catalysis. The elucidations of the molecular mechanisms by which these events govern the function and substrate specificity of GTs represent a major challenge.
    Article · Oct 2016
    • "The fourth ORF (A3ECDRAFT_0839) encoded a putative α-mannosyltransferase PimA (showed 49 % identity with homolog Rv2610c in M. tuberculosis H37Rv). Genetic evidences have showed that the pimA ortholog (RV2610c) in M. tuberculosis H37Rv encoded an essential enzyme for mycobacterial growth that initiates the biosynthetic pathway of PIMs [86, 87]. Therefore in C. ulceribovis, the presence of pgsA (A3E CDRAFT_0837) and pimA (A3ECDRAFT_0839) genes together within a cluster of genes suggested that PgsA (A3ECDRAFT_0837) may be a phosphatidylinositol synthase involved in PI biosynthesis which could be mannosylated by PimA (A3ECDRAFT_0839) leading to the synthesis of PIM. "
    [Show abstract] [Hide abstract] ABSTRACT: Corynebacterium ulceribovis strain IMMIB L-1395T (= DSM 45146T) is an aerobic to facultative anaerobic, Gram-positive, non-spore-forming, non-motile rod-shaped bacterium that was isolated from the skin of the udder of a cow, in Schleswig Holstein, Germany. The cell wall of C. ulceribovis contains corynemycolic acids. The cellular fatty acids are those described for the genus Corynebacterium, but tuberculostearic acid is not present. Here we describe the features of C. ulceribovis strain IMMIB L-1395T, together with genome sequence information and its annotation. The 2,300,451 bp long genome containing 2,104 protein-coding genes and 54 RNA-encoding genes and is part of the Genomic Encyclopedia of Type Strains, Phase I: the one thousand microbial genomes (KMG) project. Electronic supplementary material The online version of this article (doi:10.1186/s40793-015-0036-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · Sep 2015
    • "Moreover, labeling experiments with deuterated inositol indicated that the source of this metabolite is solely exogenous. In some bacteria, such as in mycobacteria, PI is further built up with other sugar residues, such as mannose, to form phosphatidyl-myoinositol mannosides (PIMs) [42]. In our study, no other lipids were seen to incorporate labeled myo-inositol, and so further derivatization of the inositol-containing lipids to form other major lipid components is not expected to occur in T. forsythia. "
    [Show abstract] [Hide abstract] ABSTRACT: Unique phosphodihydroceramides containing phosphoethanolamine and glycerol have been previously described in Porphyromonas gingivalis. Importantly, they were shown to possess pro-inflammatory properties. Other common human bacteria were screened for the presence of these lipids, and they were found, amongst others, in the oral pathogen Tannerella forsythia. To date, no detailed study into the lipids of this organism has been performed. Lipids were extracted, separated and purified by HPTLC, and analyzed using GC-MS, ESI-MS and NMR. Of special interest was how T. forsythia acquires the metabolic precursors for the lipids studied here. This was assayed by radioactive and stable isotope incorporation using carbon-14 and deuterium labeled myo-inositol, added to the growth medium. T. forsythia synthesizes two phosphodihydroceramides (Tf GL1, Tf GL2) which are constituted by phospho-myo-inositol linked to either a 17-, 18-, or 19-carbon sphinganine, N-linked to either a branched 17:0(3-OH) or a linear 16:0(3-OH) fatty acid which, in Tf GL2, is, in turn, ester-substituted with a branched 15:0 fatty acid. T. forsythia lacks the enzymatic machinery required for myo-inositol synthesis but was found to internalize inositol from the medium for the synthesis of both Tf GL1 and Tf GL2. The study describes two novel glycolipids in T. forsythia which could be essential in this organism. Their synthesis could be reliant on an external source of myo-inositol. The effects of these unique lipids on the immune system and their role in bacterial virulence could be relevant in the search for new drug targets. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Aug 2015
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