Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity
Human UDP-glucuronosyltransferases (UGTs) play a pivotal role in phase II metabolism by catalyzing the glucuronidation of endobiotics and xenobiotics. The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-i...
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| description | Human UDP-glucuronosyltransferases (UGTs) play a pivotal role in phase II metabolism by catalyzing the glucuronidation of endobiotics and xenobiotics. The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-isoform hetero-dimerization of UGT1A1, 1A9 and 2B7, including the wild type (1A1*1, 1A9*1 and 2B7*1) and the naturally occurring (1A1*1b, 1A9*2/*3/*5 and 2B7*71S/*2/*5) variants. The related enzymes were double expressed in Bac-to-Bac systems. The fluorescence resonance energy transfer (FRET) technique and co-immunoprecipitation (Co-IP) revealed stable hetero-dimerization of UGT1A1, 1A9 and 2B7 allozymes. Variable FRET efficiencies and donor-acceptor distances suggested that genetic polymorphisms resulted in altered affinities to the target protein. In addition, the metabolic activities of UGTs were differentially altered upon hetero-dimerization via double expression systems. Moreover, protein interactions also changed the regioselectivity of UGT1A9 for querectin glucuronidation. These findings provide in-depth understanding of human UGT dimerization as well as clues for complicated UGT dependent metabolism in humans. |
| doi_str_mv | 10.1038/srep34450 |
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The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-isoform hetero-dimerization of UGT1A1, 1A9 and 2B7, including the wild type (1A1*1, 1A9*1 and 2B7*1) and the naturally occurring (1A1*1b, 1A9*2/*3/*5 and 2B7*71S/*2/*5) variants. The related enzymes were double expressed in Bac-to-Bac systems. The fluorescence resonance energy transfer (FRET) technique and co-immunoprecipitation (Co-IP) revealed stable hetero-dimerization of UGT1A1, 1A9 and 2B7 allozymes. Variable FRET efficiencies and donor-acceptor distances suggested that genetic polymorphisms resulted in altered affinities to the target protein. In addition, the metabolic activities of UGTs were differentially altered upon hetero-dimerization via double expression systems. Moreover, protein interactions also changed the regioselectivity of UGT1A9 for querectin glucuronidation. These findings provide in-depth understanding of human UGT dimerization as well as clues for complicated UGT dependent metabolism in humans.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep34450</identifier><identifier>PMID: 27857056</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/337 ; 631/45 ; 82/80 ; Dimerization ; Energy transfer ; Enzymes ; Fluorescence resonance energy transfer ; Humanities and Social Sciences ; Immunoprecipitation ; Isoenzymes ; Metabolism ; multidisciplinary ; Oligomerization ; Protein interaction ; Science ; Xenobiotics</subject><ispartof>Scientific reports, 2016-11, Vol.6 (1), p.34450-34450, Article 34450</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Nov 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-58456d21de2e4586fb4d49274b1af95cc6d95232addeff634fd3ee661598be033</citedby><cites>FETCH-LOGICAL-c504t-58456d21de2e4586fb4d49274b1af95cc6d95232addeff634fd3ee661598be033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114717/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114717/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,27907,27908,41103,42172,51559,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27857056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yuan, Ling-Min</creatorcontrib><creatorcontrib>Gao, Zhang-Zhao</creatorcontrib><creatorcontrib>Sun, Hong-Ying</creatorcontrib><creatorcontrib>Qian, Sai-Nan</creatorcontrib><creatorcontrib>Xiao, Yong-Sheng</creatorcontrib><creatorcontrib>Sun, Lian-Li</creatorcontrib><creatorcontrib>Zeng, Su</creatorcontrib><title>Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Human UDP-glucuronosyltransferases (UGTs) play a pivotal role in phase II metabolism by catalyzing the glucuronidation of endobiotics and xenobiotics. 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The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-isoform hetero-dimerization of UGT1A1, 1A9 and 2B7, including the wild type (1A1*1, 1A9*1 and 2B7*1) and the naturally occurring (1A1*1b, 1A9*2/*3/*5 and 2B7*71S/*2/*5) variants. The related enzymes were double expressed in Bac-to-Bac systems. The fluorescence resonance energy transfer (FRET) technique and co-immunoprecipitation (Co-IP) revealed stable hetero-dimerization of UGT1A1, 1A9 and 2B7 allozymes. Variable FRET efficiencies and donor-acceptor distances suggested that genetic polymorphisms resulted in altered affinities to the target protein. In addition, the metabolic activities of UGTs were differentially altered upon hetero-dimerization via double expression systems. Moreover, protein interactions also changed the regioselectivity of UGT1A9 for querectin glucuronidation. These findings provide in-depth understanding of human UGT dimerization as well as clues for complicated UGT dependent metabolism in humans.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27857056</pmid><doi>10.1038/srep34450</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/337 631/45 82/80 Dimerization Energy transfer Enzymes Fluorescence resonance energy transfer Humanities and Social Sciences Immunoprecipitation Isoenzymes Metabolism multidisciplinary Oligomerization Protein interaction Science Xenobiotics |
| title | Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity |
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