Article

Molecular basis of phosphatidyl-myo-inositol mannoside biosynthesis and regulation in mycobacteria.

Unidad de Biofisica, Centro Mixto Consejo Superior de Investigaciones Cientificas-Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Bizkaia 48940, Spain.
Journal of Biological Chemistry (Impact Factor: 4.6). 10/2010; 285(44):33577-83. 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.

0 Followers
 · 
122 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Phosphatidylinositol mannosides are essential structural components of the mycobacterial cell envelope. They are implicated in host-pathogen interactions during infection and serve as a basis for biosynthesis of other unique molecules with immunomodulatory properties- mycobacterial lipopolysaccharides lipoarabinomannan and lipomannan. Acyltransferase Rv2611 is involved in one of the initial steps in the assembly of these molecules in Mycobacterium tuberculosis - the attachment of an acyl group to position-6 of the 2-linked mannosyl residue of the phosphatidylinositol mannoside anchor. Although the function of this enzyme was annotated 10 years ago, it has never been completely biochemically characterized due to lack of the pure protein. We have successfully overexpressed and purified MSMEG_2934, the ortholog of Rv2611c from the non-pathogenic model organism M. smegmatis mc(2)155 using mycobacterial pJAM2 expression system, which allowed confirmation of its in vitro acyltransferase activity, and establishment of its substrate specificity.
    Protein Expression and Purification 05/2014; DOI:10.1016/j.pep.2014.04.014 · 1.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Phosphatidylinositol mannosides are essential structural components of the mycobacterial cell envelope. They are implicated in host-pathogen interactions during infection and serve as a basis for biosynthesis of other unique molecules with immunomodulatory properties- mycobacterial lipopolysaccharides lipoarabinomannan and lipomannan. Acyltransferase Rv2611 is involved in one of the initial steps in the assembly of these molecules in Mycobacterium tuberculosis - the attachment of an acyl group to position-6 of the 2-linked mannosyl residue of the phosphatidylinositol mannoside anchor. Although the function of this enzyme was annotated 10 years ago, it has never been completely biochemically characterized due to lack of the pure protein. We have successfully overexpressed and purified MSMEG_2934, the ortholog of Rv2611c from the non-pathogenic model organism M. smegmatis mc2155 using mycobacterial pJAM2 expression system, which allowed confirmation of its in vitro acyltransferase activity, and establishment of its substrate specificity.
    Protein Expression and Purification 01/2014; · 1.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis is the causative agent of tuberculosis disease, which has developed a myriad of exceptional features contributing to its survival within the hostile environment of host cell. Unique cell wall structure with high lipid content plays an imperative role in the pathogenicity of mycobacteria. Cell wall components of MTB such as lipoarabinomannan and Trehalose dimycolate (cord factor) are virulent in nature apart from its virulence genes. Virulent effect of these factors on host cells reduces host cell immunity. LAM has been known to inhibit phagosome maturation by inhibiting the Ca(2+)/calmodulin phosphatidyl inositol-3-kinase hvps34 pathways. Moreover, TDM (Trehalose dimycolate) also inhibits fusion between phospholipid vesicles and migration of polymorphonuclear neutrophils. The objective of this paper is to understand the virulence of LAM and cord factor on host cell which might be helpful to design an effective drug against tuberculosis.
    01/2011; 2011:274693. DOI:10.4061/2011/274693