Structure, function, and inhibition of drug reactivating human gut microbial β-glucuronidases

Biernat, Kristen A.; Pellock, Samuel J.; Bhatt, Aadra P.; Bivins, Marissa M.; Walton, William G.; Tran, Bich Ngoc T.; Wei, Lianjie; Snider, Michael C.; Cesmat, Andrew P.; Tripathy, Ashutosh; Erie, Dorothy A.; Redinbo, Matthew R.

doi:10.1038/s41598-018-36069-w

Title: Structure, function, and inhibition of drug reactivating human gut microbial β-glucuronidases

Journal Article · Tue Jan 29 00:00:00 EST 2019 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-36069-w· OSTI ID:1497166

Biernat, Kristen A. ^[1]; Pellock, Samuel J. ^[1]; Bhatt, Aadra P. ^[1]; Bivins, Marissa M. ^[1]; Walton, William G. ^[1]; Tran, Bich Ngoc T. ^[1]; Wei, Lianjie ^[1]; Snider, Michael C. ^[1]; Cesmat, Andrew P. ^[1]; Tripathy, Ashutosh ^[1]; Erie, Dorothy A. ^[1]; Redinbo, Matthew R. ^[1]

Univ. of North Carolina, Chapel Hill, NC (United States)

Bacterial β-glucuronidase (GUS) enzymes cause drug toxicity by reversing Phase II glucuronidation in the gastrointestinal tract. While many human gut microbial GUS enzymes have been examined with model glucuronide substrates like p-nitrophenol-β-D-glucuronide (pNPG), the GUS orthologs that are most efficient at processing drug-glucuronides remain unclear. Here we present the crystal structures of GUS enzymes from human gut commensals Lactobacillus rhamnosus, Ruminococcus gnavus, and Faecalibacterium prausnitzii that possess an active site loop (Loop 1; L1) analogous to that found in E. coli GUS, which processes drug substrates. We also resolve the structure of the No Loop GUS from Bacteroides dorei. We then compare the pNPG and diclofenac glucuronide processing abilities of a panel of twelve structurally diverse GUS proteins, and find that the new L1 GUS enzymes presented here process small glucuronide substrates inefficiently compared to previously characterized L1 GUS enzymes like E. coli GUS. We further demonstrate that our GUS inhibitors, which are effective against some L1 enzymes, are not potent towards all. Our findings pinpoint active site structural features necessary for the processing of drug-glucuronide substrates and the inhibition of such processing.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Cancer Institute (NCI)

Grant/Contract Number:: CA098468; CA207416; P30CA016086

OSTI ID:: 1497166

Journal Information:: Scientific Reports, Vol. 9, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 42 works

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