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A common polymorphic variant of UGT 1A5 displays increased activity due to optimized cofactor binding
Author(s) -
Yang Fan,
Machalz David,
Wang Sisi,
Li Zhengyi,
Wolber Gerhard,
Bureik Matthias
Publication year - 2018
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13072
Subject(s) - mutant , enzyme , chemistry , biochemistry , uridine diphosphate , glucuronidation , uridine , mutation , cofactor , biology , gene , rna , microsome
Uridine diphosphate‐glucuronosyltransferases ( UGT s) are the most important phase II enzymes in human drug metabolism. Using permeabilized recombinant fission yeast cells (enzyme bags), we demonstrate that UGT 1A5 can catalyze an N ‐glucuronidation reaction. We characterized two new polymorphic UGT 1A5 variants: a common ninefold mutant ( UGT 1A5*8) with double‐fold activity and a much rarer sixfold mutant ( UGT 1A5*9), which has the same activity as the wild‐type. Molecular modeling studies indicate that the minor effects of all mutations, except for Gly259Arg, are due to their distance to the substrate binding site. Extensive molecular dynamics simulations revealed that the Gly259Arg mutation stabilizes helix Q through a newly formed hydrogen bonding network, which places the cofactor in a much more favorable geometry in UGT 1A5*8 as compared to the wild‐type.