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PDBsum entry 4jhz
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Hydrolase/hydrolase inhibitor
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PDB id
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4jhz
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References listed in PDB file
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Key reference
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Title
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Molecular insights into microbial β-Glucuronidase inhibition to abrogate cpt-11 toxicity.
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Authors
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A.B.Roberts,
B.D.Wallace,
M.K.Venkatesh,
S.Mani,
M.R.Redinbo.
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Ref.
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Mol Pharmacol, 2013,
84,
208-217.
[DOI no: ]
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PubMed id
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Abstract
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Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota
appear to play important roles in drug-induced epithelial cell toxicity in the
gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the
nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal
of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases
in the GI lumen can significantly damage the intestinal epithelium. Furthermore,
selective disruption of bacterial β-glucuronidases by small molecule inhibitors
alleviates these side effects, which, for CPT-11
{7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we
characterize novel microbial β-glucuronidase inhibitors that inhibit
Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2
μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM.
All compounds are selective for E. coli β-glucuronidase without inhibiting
purified mammalian β-glucuronidase, and they do not impact the survival of
either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of
one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts
and orders only a portion of the "bacterial loop" present in
microbial, but not mammalian, β-glucuronidases. The most potent compound
examined in this group was found to protect mice against CPT-11-induced
diarrhea. Taken together, these data advance our understanding of the chemical
and structural basis of selective microbial β-glucuronidase inhibition, which
may improve human drug efficacy and toxicity.
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