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Structure of E. coli beta-Glucuronidase bound with a novel, potent inhibitor 2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-N-[(1S,2S,5S)-2,5-dimethoxycyclohexyl]acetamideStructure of E. coli beta-Glucuronidase bound with a novel, potent inhibitor 2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-N-[(1S,2S,5S)-2,5-dimethoxycyclohexyl]acetamide
Structural highlights
FunctionPublication Abstract from PubMedBacterial beta-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 beta-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial beta-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 beta-glucuronidase inhibitors that inhibit Escherichia coli beta-glucuronidase in vitro with Ki values between 180 nM and 2 muM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli beta-glucuronidase without inhibiting purified mammalian beta-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 A resolution crystal structure of one inhibitor bound to E. coli beta-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, beta-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 beta-glucuronidase inhibition, which may improve human drug efficacy and toxicity. Molecular Insights into Microbial beta-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity.,Roberts AB, Wallace BD, Venkatesh MK, Mani S, Redinbo MR Mol Pharmacol. 2013 Aug;84(2):208-17. doi: 10.1124/mol.113.085852. Epub 2013 May , 20. PMID:23690068[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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