Structure, function, and inhibition of drug reactivating human gut microbial ?-glucuronidases [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 630.9 Agriculture and related technologies

Thông tin xuất bản: Bethesda, Md. : Oak Ridge, Tenn. : National Institutes of Health (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019

Mô tả vật lý: Size: Article No. 825 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 260084

 Bacterial ?-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-?-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 <
 em>
 Lactobacillus rhamnosus, Ruminococcus gnavus<
 /em>
 , and <
 em>
 Faecalibacterium prausnitzii<
 /em>
  that possess an active site loop (Loop 1
  L1) analogous to that found in <
 em>
 E. coli<
 /em>
  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 <
 em>
 E. coli<
 /em>
  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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