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PDBsum entry 2pqc
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References listed in PDB file
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Key reference
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Title
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Differential inhibition of class i and class ii 5-Enolpyruvylshikimate-3-Phosphate synthases by tetrahedral reaction intermediate analogues.
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Authors
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T.Funke,
M.L.Healy-Fried,
H.Han,
D.G.Alberg,
P.A.Bartlett,
E.Schönbrunn.
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Ref.
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Biochemistry, 2007,
46,
13344-13351.
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PubMed id
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Abstract
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The shikimate pathway enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSP
synthase or EPSPS) is best known as the target of the herbicide glyphosate.
EPSPS is also considered an attractive target for the development of novel
antibiotics since the pathogenicity of many microorganisms depends on the
functionality of the shikimate pathway. Here, we have investigated the
inhibitory potency of stable fluorinated or phosphonate-based analogues of the
tetrahedral reaction intermediate (TI) in a parallel study utilizing class I
(glyphosate-sensitive) and class II (glyphosate-tolerant) EPSPS. The
(R)-difluoromethyl and (R)-phosphonate analogues of the TI are the most potent
inhibitors of EPSPS described to date. However, we found that class II EPSPS are
up to 400 times less sensitive to inhibition by these TI analogues. X-ray
crystallographic data revealed that the conformational changes of active site
residues observed upon inhibitor binding to the representative class I EPSPS
from Escherichia coli do not occur in the prototypical class II enzyme from
Agrobacterium sp. strain CP4. It appears that because the active sites of class
II EPSPS do not possess the flexibility to accommodate these TI analogues, the
analogues themselves undergo conformational changes, resulting in less favorable
inhibitory properties. Since pathogenic microorganisms such as Staphylococcus
aureus utilize class II EPSPS, we conclude that the rational design of novel
EPSPS inhibitors with potential as broad-spectrum antibiotics should be based on
the active site structures of class II EPSP synthases.
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