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PDBsum entry 2fqt
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References listed in PDB file
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Key reference
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Title
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Design and synthesis of substrate and intermediate analogue inhibitors of s-Ribosylhomocysteinase.
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Authors
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G.Shen,
R.Rajan,
J.Zhu,
C.E.Bell,
D.Pei.
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Ref.
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J Med Chem, 2006,
49,
3003-3011.
[DOI no: ]
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PubMed id
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Abstract
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S-Ribosylhomocysteinase (LuxS) catalyzes the cleavage of the thioether linkage
in S-ribosylhomocysteine (SRH) to produce homocysteine and
4,5-dihydroxy-2,3-pentanedione, the precursor of autoinducer 2. Inhibitors of
LuxS should interfere with bacterial interspecies communication and potentially
provide a novel class of antibacterial agents. LuxS utilizes a divalent metal
ion as a Lewis acid during catalysis. In this work, a series of structural
analogues of the substrate SRH and a 2-ketone intermediate were designed and
synthesized. Kinetic studies indicate that the compounds act as reversible,
competitive inhibitors against LuxS, with the most potent inhibitors having K(I)
values in the submicromolar range. These represent the most potent LuxS
inhibitors that have been reported to date. Cocrystal structures of LuxS bound
with two of the inhibitors largely confirmed the design principles, i.e., the
importance of both the homocysteine and ribose moieties in high-affinity binding
to the LuxS active site.
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