β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut

Punsaldulam Dashnyam, Ramesh Mudududdla, Tung-Ju Hsieh, Ting-Chien Lin, Hsien-Ya Lin, Peng-Yuan Chen, Chia-Yi Hsu, Chun-Hung Lin

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

Gut bacterial β-D-glucuronidases (GUSs) catalyze the removal of glucuronic acid from liver-produced β-D-glucuronides. These reactions can have deleterious consequences when they reverse xenobiotic metabolism. The human gut contains hundreds of GUSs of variable sequences and structures. To understand how any particular bacterial GUS(s) contributes to global GUS activity and affects human health, the individual substrate preference(s) must be known. Herein, we report that representative GUSs vary in their ability to produce various xenobiotics from their respective glucuronides. To attempt to explain the distinct substrate preference, we solved the structure of a bacterial GUS complexed with coumarin-3-β-D-glucuronide. Comparisons of this structure with other GUS structures identified differences in loop 3 (or the α2-helix loop) and loop 5 at the aglycone-binding site, where differences in their conformations, hydrophobicities and flexibilities appear to underlie the distinct substrate preference(s) of the GUSs. Additional sequence, structural and functional analysis indicated that several groups of functionally related gut bacterial GUSs exist. Our results pinpoint opportunistic gut bacterial GUSs as those that cause xenobiotic-induced toxicity. We propose a structure-activity relationship that should allow both the prediction of the functional roles of GUSs and the design of selective inhibitors.

Original languageEnglish
Article number16372
Number of pages12
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 6 Nov 2018
Externally publishedYes

Cite this