Pinpoint Structural Features
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.
The Redinbo Group
Published in Scientific Reports, researchers in the Redinbo Group, in collaboration with Professor Erie, and led by postdoctoral research assistant Kristen Biernat, 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. The group members also resolve the structure of the No Loop GUS from Bacteroides dorei.
Subsequently, the group members 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. They further demonstrate that their GUS inhibitors, which are effective against some L1 enzymes, are not potent towards all.
These findings pinpoint active site structural features necessary for the processing of drug-glucuronide substrates and the inhibition of such processing.