2GYO

Methanethiol-Cys 112 Inhibition Complex of E. Coli Ketoacyl Synthase III (FabH) and Coenzyme A

Summary for 2GYO

• Entry DOI: 10.2210/pdb2gyo/pdb
• Related: 1EBL 1HND
• Descriptor: 3-oxoacyl-[acyl-carrier-protein] synthase 3, COENZYME A, METHANETHIOL, ... (5 entities in total)
• Functional Keywords: fatty acid biosynthesis, alkyl-coa-disulfide, mechanism-based inhibitor, mycobacterium tuberculosis, transferase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P0A6R0
• Total number of polymer chains: 2
• Total formula weight: 68101.82

Authors

Alhamadsheh, M.M.,Musayev, F.,Komissarov, A.A.,Sachdeva, S.,Wright, H.T.,Scarsdale, N.,Florova, G.,Reynolds, K.A. (deposition date: 2006-05-09, release date: 2007-06-05, Last modification date: 2011-07-13)

Primary citation

Alhamadsheh, M.M.,Musayev, F.,Komissarov, A.A.,Sachdeva, S.,Wright, H.T.,Scarsdale, N.,Florova, G.,Reynolds, K.A.
Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes.
Chem.Biol., 14:513-524, 2007

PubMed 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 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.

PubMed: 17524982
DOI: 10.1016/j.chembiol.2007.03.013

Experimental method

X-RAY DIFFRACTION (2 Å)