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

Biochemical Pharmacology
Lingmin YuanSu Zeng

Abstract

Most human UDP-glucuronosyltransferase (UGT; EC 2.4.1.17) genes contain non-synonymous single nucleotide polymorphisms (nsSNPs) which cause amino acid substitutions. Allelic variants caused by nsSNPs may exhibit absent or reduced enzyme activity. UGT2B7 is one of the most important UGTs that glucuronidates abundant endobiotics and xenobiotics, such as estriol, morphine, and anticancer drugs. Three nsSNPs, UGT2B7*71S (211G>T), UGT2B7*2 (802C>T) and UGT2B7*5 (1192G>A) are observed in the UGT2B7 gene, and they code for allozymes UGT2B7*71S (A71S), UGT2B7*2 (H268Y), and UGT2B7*5 (D398N). UGT2B7 has been observed to form oligomers that affect its enzymatic activity and in this study, we investigated protein-protein interactions among UGT2B7 allozymes wild type (WT), A71S, H268Y and D398N, by performing a systematic quantitative fluorescence resonance energy transfer (FRET) analysis in combination with co-immunoprecipitation assay. Quantitative FRET analysis revealed that UGT2B7 allozymes formed homo- and hetero-dimers and showed distinct features in donor-acceptor distances. Both codon 71 and codon 268 in the N-terminal domain were involved in the dimeric interaction. Co-immunoprecipitation experiments also proved that UGT2B7 allozy...Continue Reading

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Citations

Nov 6, 2015·Phytotherapy Research : PTR·Qian ZhangWei-Ming Wang
Nov 9, 2016·Frontiers in Pharmacology·Ryoichi FujiwaraMiki Nakajima
Mar 14, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Da-Wei ChenZhong-Ze Fang
Dec 23, 2017·Clinical and Experimental Pharmacology & Physiology·Bao-Xia HeHui Liu
Feb 7, 2019·Physiological Reviews·Robyn MeechPeter I Mackenzie
Jan 2, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ian CookThomas S Leyh
Dec 15, 2017·Biopharmaceutics & Drug Disposition·Jin-Zi JiHong-Guang Xie

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