Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid

Omita A. Trivedi, Pooja Arora, Archana Vats, Mohd Zeeshan Ansari, Rashmi Tickoo, Vijayalakshmi Sridharan, Debasisa Mohanty, Rajesh S. Gokhale

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Mycobacterium tuberculosis cell envelope is a treasure house of biologically active lipids of fascinating molecular architecture. Although genetic studies have alluded to an array of genes in biosynthesis of complex lipids, their mechanistic, structural, and biochemical principles have not been investigated. Here, we have dissected the molecular logic underlying the biosynthesis of a virulence lipid phthiocerol dimycocerosate (PDIM). Cell-free reconstitution studies demonstrate that polyketide synthases, which are usually involved in the biosynthesis of secondary metabolites, are responsible for generating complex lipids in mycobacteria. We show that PapA5 protein directly transfers the protein bound mycocerosic acid analogs on phthiocerol to catalyze the final esterification step. Based on precise identification of biological functions of proteins from Pps cluster, we have rationally produced a nonmethylated variant of mycocerosate esters. Apart from elucidating mechanisms that generate chemical heterogeneity with PDIMs, this study also presents an attractive approach to explore host-pathogen interactions by altering mycobacterial surface coat.

Original languageEnglish (US)
Pages (from-to)631-643
Number of pages13
JournalMolecular Cell
Volume17
Issue number5
DOIs
StatePublished - Mar 4 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Trivedi, O. A., Arora, P., Vats, A., Ansari, M. Z., Tickoo, R., Sridharan, V., Mohanty, D., & Gokhale, R. S. (2005). Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid. Molecular Cell, 17(5), 631-643. https://doi.org/10.1016/j.molcel.2005.02.009