Mycobacterial phenolic glycolipid virulence factor biosynthesis: mechanism and small-molecule inhibition of polyketide chain initiation. Academic Article uri icon

Overview

abstract

  • Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by Mycobacterium tuberculosis, M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-S-enzyme covalent intermediate in the p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.

publication date

  • December 27, 2007

Research

keywords

  • Coenzyme A Ligases
  • Enzyme Inhibitors
  • Glycolipids
  • Macrolides
  • Mycobacterium tuberculosis
  • Phenols
  • Virulence Factors

Identity

PubMed Central ID

  • PMC2276623

Scopus Document Identifier

  • 38349074340

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2007.11.010

PubMed ID

  • 18158259

Additional Document Info

volume

  • 15

issue

  • 1