Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes

Chem Biol. 2007 May;14(5):513-24. doi: 10.1016/j.chembiol.2007.03.013.


The first step of the reaction catalyzed by the homodimeric FabH from a dissociated fatty acid synthase is acyl transfer from acyl-CoA to an active site cysteine. We report that C1 to C10 alkyl-CoA disulfides irreversibly inhibit Escherichia coli FabH (ecFabH) and Mycobacterium tuberculosis FabH with relative efficiencies that reflect these enzymes' differential acyl-group specificity. Crystallographic and kinetic studies with MeSSCoA show rapid inhibition of one monomer of ecFabH through formation of a methyl disulfide conjugate with this cysteine. Reaction of the second subunit with either MeSSCoA or acetyl-CoA is much slower. In the presence of malonyl-ACP, the acylation rate of the second subunit is restored to that of the native ecFabH. These observations suggest a catalytic model in which a structurally disordered apo-ecFabH dimer orders on binding either the first substrate, acetyl-CoA, or the inhibitor MeSSCoA, and is restored to a disordered state on binding of malonyl-ACP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
  • Acylation
  • Binding Sites
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Disulfides / chemical synthesis*
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Fluorescence
  • Fluorometry
  • Indicators and Reagents
  • Kinetics
  • Models, Molecular
  • Streptomyces / drug effects
  • Streptomyces / enzymology


  • Disulfides
  • Enzyme Inhibitors
  • Indicators and Reagents
  • 3-ketoacyl-acyl carrier protein synthase III
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
  • Cysteine

Associated data

  • PDB/2GYO