Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity

Yuan, Lingmin; Qian, Sainan; Xiao, Yongsheng; Sun, Hongying; Zeng, Su

doi:10.1016/j.bcp.2015.03.002

Cited by 26 publications

(38 citation statements)

References 41 publications

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“…confirmed the existence of protein-protein interactions between wild type UGT2B7 and several UGT1A members, using Co-IP24. Homo- and hetero-dimerization of UGT1A1 and UGT1A9 allozymes25, as well as UGT2B7 allozymes12, have recently been reported by our research team. Furthermore, increasing evidence suggests that oligomerization remarkably affects the catalytic activity of individual enzymes involved in the oligomerization system.…”

supporting

confidence: 81%

“…Meanwhile, estrone, mycophenolic acid, raloxifene and retinoic acid are typical substrates for UGT1A95789. UGT2B7 is known as the most important human UGT enzyme responsible for phase II metabolism of most clinically used drugs, including morphine, zidovudine, and carbamazepine10111213.…”

mentioning

confidence: 99%

“…Dimerization of two different inactive mutants of UGT2B1 results in enzymatic activity recovery26. Double expressed wild type UGT2B7 with its allelic variants show significant differences in kinetic behaviors for zidovudine glucuronidation, compared with the single expressed form12. Therefore, protein-protein interactions of UGTs play key roles in glucuronidation activity regulation.…”

mentioning

confidence: 99%

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Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity

Yuan

Gao

Sun

et al. 2016

Sci Rep

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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.

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supporting

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity

Yuan

Gao

Sun

et al. 2016

Sci Rep

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“…Additionally, the authors confirmed heterodimer interactions between UGT1A1 and the UGT1A3, 1A4, 1A6, 1A7, 1A8, 1A9, and UGT1A10 isoforms. More recently, Yuan et al used FRET to demonstrate that UGT2B7 was able to form homo oligomers with both wild-type and mutant forms of the enzyme, which had the possibility of affecting zidovudine glucuronidation (Yuan et al, 2015). Yuan further went on to demonstrate that the UGT isoforms UGT1A1, 1A9, and 2B7 were all able to form heterodimeric complexes, expanding on their previous work that examined homodimerization in this enzyme class .…”

Section: Fluorescence Technologiesmentioning

confidence: 99%

“…Their FRET analysis demonstrated homo-oligomerization of all UGT1A isoforms as well as hetero-oligomerization of UGT1A1 with the other UGT1A isoforms. The FRET analysis conducted by a different research group indicated that not only UGT1As, but also human UGT2B7 formed homo-oligomers in SF9 cells (Yuan et al, 2015;Liu Y.Q. et al, 2016).…”

Section: Fluorescence Resonance Energy Transfer (Fret)mentioning

confidence: 99%

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

Pandey¹,

Henderson²,

Ishii³

et al. 2018

Frontiers Research Topics

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Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate

Huang

et al. 2018

Biopharm & Drug Disp

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Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean V value of 120.9 pmol/min/mg protein, 3- to 12-fold higher than that of the other rUGT isoforms tested. According to relative activity factor approach, the relative contribution of rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed Michaelis-Menten kinetics with a mean K value of 372.9 μM and 296.4 μM for pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The formation of CAG was significantly inhibited by azidothymidine and gemfibrozil (well-characterized UGT2B7 substrates) in a concentration-dependent manner, or by fluconazole (a typical UGT2B7-selective inhibitor) in a time-dependent manner, for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs and rUGT2B7 in a concentration-dependent manner, indicating that CCA is a substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug-drug interactions between clopidogrel and the other substrate drugs of UGT2B7.

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Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity

Cited by 26 publications

References 41 publications

Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity

Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate

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