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

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 u...

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Autores principales:	Punsaldulam Dashnyam, Ramesh Mudududdla, Tung-Ju Hsieh, Ting-Chien Lin, Hsien-Ya Lin, Peng-Yuan Chen, Chia-Yi Hsu, Chun-Hung Lin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Xenobiotic-induced Toxicity Aglycone Binding Site (ABS) Distinct Substrate Preferences CP GU Xenobiotic Glucuronidation Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b6371ff0cd6400d83e8e0397189f8c8
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spelling	oai:doaj.org-article:0b6371ff0cd6400d83e8e0397189f8c82021-12-02T15:07:50Zβ-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut10.1038/s41598-018-34678-z2045-2322https://doaj.org/article/0b6371ff0cd6400d83e8e0397189f8c82018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34678-zhttps://doaj.org/toc/2045-2322Abstract 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.Punsaldulam DashnyamRamesh MudududdlaTung-Ju HsiehTing-Chien LinHsien-Ya LinPeng-Yuan ChenChia-Yi HsuChun-Hung LinNature PortfolioarticleXenobiotic-induced ToxicityAglycone Binding Site (ABS)Distinct Substrate PreferencesCP GUXenobiotic GlucuronidationMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Xenobiotic-induced Toxicity Aglycone Binding Site (ABS) Distinct Substrate Preferences CP GU Xenobiotic Glucuronidation Medicine R Science Q
spellingShingle	Xenobiotic-induced Toxicity Aglycone Binding Site (ABS) Distinct Substrate Preferences CP GU Xenobiotic Glucuronidation Medicine R Science Q Punsaldulam Dashnyam Ramesh Mudududdla Tung-Ju Hsieh Ting-Chien Lin Hsien-Ya Lin Peng-Yuan Chen Chia-Yi Hsu Chun-Hung Lin β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
description	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.
format	article
author	Punsaldulam Dashnyam Ramesh Mudududdla Tung-Ju Hsieh Ting-Chien Lin Hsien-Ya Lin Peng-Yuan Chen Chia-Yi Hsu Chun-Hung Lin
author_facet	Punsaldulam Dashnyam Ramesh Mudududdla Tung-Ju Hsieh Ting-Chien Lin Hsien-Ya Lin Peng-Yuan Chen Chia-Yi Hsu Chun-Hung Lin
author_sort	Punsaldulam Dashnyam
title	β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
title_short	β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
title_full	β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
title_fullStr	β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
title_full_unstemmed	β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
title_sort	β-glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/0b6371ff0cd6400d83e8e0397189f8c8
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_version_	1718388364933070848

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

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