A rare UGT2B7 variant creates a novel N-glycosylation site at codon 121 with impaired enzyme activity

Authors: Girard-Bock, CamilleBenoît-Biancamano, Marie-OdileVilleneuve, LyneDesjardins, SylvieGuillemette, Chantal
Abstract: UDP-glucuronosyltransferase (UGT) superfamily are glycoproteins resident of the endoplasmic reticulum membranes that undergo post-translational modifications (PTM). UGT2B7 is of particular interest because of its action on a wide variety of drugs. Most studies currently survey common variants and are only examining a small fraction of the genetic diversity. However, rare variants (frequency <1%) might have significant effect as they are predicted to greatly outnumber common variants in the human genome. Here, we discovered a rare single nucleotide UGT2B7 variant of potential pharmacogenetic relevance that encodes a nonconservative amino acid substitution at codon 121. This low-frequency variation, found in two individuals of a population of 305 healthy volunteers, leads to the translation of an asparagine (Asn) instead of an aspartic acid (Asp) (UGT2B7 p.D121N). This amino acid change was predicted to create a putative N-glycosylation motif NX(S/T) subsequently validated upon endoglycosidase H treatment of microsomal fractions and inhibition of N-glycosylation of endogenously produced UGT2B7 with tunicamycin from HEK293 cells. The presence of an additional N-linked glycan on the UGT2B7 enzyme, likely affecting proper protein folding, resulted in a significant decrease, respectively by 49 and 40%, in the formation of zidovudine and mycophenolic acid glucuronides. A systematic survey of the dbSNP database uncovered 32 rare and naturally occurring missense variations predicted to create or disrupt N-glycosylation sequence motifs in the other UGT2B enzymes. Collectively, these variants have the potential to increase the proportion of variance explained in the UGT pathway due to changes in PTM such as N-linked glycosylation with consequences on drug metabolism.
Document Type: Article de recherche
Issue Date: 12 September 2016
Open Access Date: 12 September 2017
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/10968
This document was published in: Drug metabolism and disposition, (2016)
https://doi.org/10.1124/dmd.116.071860
American Society for Pharmacology and Experimental Therapeutics
Alternative version: 10.1124/dmd.116.071860
27612916
Collection:Articles publiés dans des revues avec comité de lecture

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