Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin

Structure. 2009 Jul 15;17(7):1004-13. doi: 10.1016/j.str.2009.04.012.

Abstract

Mycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin. Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule that mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long-chain fatty acids and provide a robust platform for the development of novel thiolactomycin analogs with high affinity for KasA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Antitubercular Agents / pharmacology*
  • Binding Sites
  • Cell Wall / metabolism*
  • Crystallography, X-Ray
  • Fatty Acids / biosynthesis
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / metabolism
  • Mycolic Acids / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Substrate Specificity
  • Thiophenes / pharmacology

Substances

  • Antitubercular Agents
  • Fatty Acids
  • Mycolic Acids
  • Thiophenes
  • thiolactomycin
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase

Associated data

  • PDB/2WGD
  • PDB/2WGE
  • PDB/2WGF
  • PDB/2WGG