Article
Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes
Chemistry & Biology
(2007)
Abstract
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 C1to 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.
Disciplines
Publication Date
May, 2007
DOI
j.chembiol.2007.03.013
Citation Information
Mamoun M. Alhamadsheh, Faik Musayev, Andrey A. Komissarov, Sarbjot Sachdeva, H. Tonie Wright, Neel Scarsdale, Galina Florova, Kevin A. Reynolds, Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes, Chemistry & Biology, Volume 14, Issue 5, 29 May 2007, Pages 513-524.