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PDBsum entry 2eft
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References listed in PDB file
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Key reference
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Title
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Alkyl-Coa disulfides as inhibitors and mechanistic probes for fabh enzymes.
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Authors
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M.M.Alhamadsheh,
F.Musayev,
A.A.Komissarov,
S.Sachdeva,
H.T.Wright,
N.Scarsdale,
G.Florova,
K.A.Reynolds.
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Ref.
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Chem Biol, 2007,
14,
513-524.
[DOI no: ]
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PubMed id
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Abstract
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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 C(1) to C(10) 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.
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Figure 1.
Figure 1. FabH Inhibition by Alkyl-CoA Disulfides
(A)
Chemical structures of alkyl-CoA disulfides 1–5.
(B)
Proposed mechanism of ecFabH inactivation by MeSSCoA (1). Cys112
of ecFabH forms a methyl disulfide conjugate upon incubation
with MeSSCoA (1). The released CoA in the CoA binding channel
may be retained or dissociated.
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Figure 5.
Figure 5. Crystal Structure of the ecFabH-MeSSCoA Soaked
Complex
Stereo figure showing electron density for (A) the
CoA and MeS-Cys112 in the A subunit of the ecFabH-MeSSCoA (1)
complex (0.16 mM) contoured at a level of 0.9σ, and (B)
electron density of the corresponding site in the B subunit.
Electron density of nearby groups is omitted for clarity.
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2007,
14,
513-524)
copyright 2007.
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