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Research ArticleArticle

Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity

Pramod C. Nair, Nuy Chau, Ross A. McKinnon and John O. Miners
Molecular Pharmacology December 2020, 98 (6) 710-718; DOI: https://doi.org/10.1124/molpharm.120.000104
Pramod C. Nair
Department of Clinical Pharmacology (P.C.N., N.C., J.O.M.) and Flinders Health and Medical Research Institute (FHMRI) Cancer Program (P.C.N., R.A.M., J.O.M.), Flinders Health and Medical Research Institute, Flinders University College of Medicine and Public Health, Flinders Medical Centre, South Australia, Australia
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Nuy Chau
Department of Clinical Pharmacology (P.C.N., N.C., J.O.M.) and Flinders Health and Medical Research Institute (FHMRI) Cancer Program (P.C.N., R.A.M., J.O.M.), Flinders Health and Medical Research Institute, Flinders University College of Medicine and Public Health, Flinders Medical Centre, South Australia, Australia
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Ross A. McKinnon
Department of Clinical Pharmacology (P.C.N., N.C., J.O.M.) and Flinders Health and Medical Research Institute (FHMRI) Cancer Program (P.C.N., R.A.M., J.O.M.), Flinders Health and Medical Research Institute, Flinders University College of Medicine and Public Health, Flinders Medical Centre, South Australia, Australia
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John O. Miners
Department of Clinical Pharmacology (P.C.N., N.C., J.O.M.) and Flinders Health and Medical Research Institute (FHMRI) Cancer Program (P.C.N., R.A.M., J.O.M.), Flinders Health and Medical Research Institute, Flinders University College of Medicine and Public Health, Flinders Medical Centre, South Australia, Australia
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Abstract

Enzymes of the human UDP-glycosyltransferase (UGT) superfamily typically catalyze the covalent addition of the sugar moiety from a UDP-sugar cofactor to relatively low–molecular weight lipophilic compounds. Although UDP-glucuronic acid (UDP-GlcUA) is most commonly employed as the cofactor by UGT1 and UGT2 family enzymes, UGT2B7 and several other enzymes can use both UDP-GlcUA and UDP-glucose (UDP-Glc), leading to the formation of glucuronide and glucoside conjugates. An investigation of UGT2B7-catalyzed morphine glycosidation indicated that glucuronidation is the principal route of metabolism because the binding affinity of UDP-GlcUA is higher than that of UDP-Glc. Currently, it is unclear which residues in the UGT2B7 cofactor binding domain are responsible for the preferential binding of UDP-GlcUA. Here, molecular dynamics (MD) simulations were performed together with site-directed mutagenesis and enzyme kinetic studies to identify residues within the UGT2B7 binding site responsible for the selective cofactor binding. MD simulations demonstrated that Arg259, which is located within the N-terminal domain, specifically interacts with UDP-GlcUA, whereby the side chain of Arg259 H-bonds and forms a salt bridge with the carboxylate group of glucuronic acid. Consistent with the MD simulations, substitution of Arg259 with Leu resulted in the loss of morphine, 4-methylumbelliferone, and zidovudine glucuronidation activity, but morphine glucosidation was preserved.

SIGNIFICANCE STATEMENT Despite the importance of uridine diphosphate glycosyltransferase (UGT) enzymes in drug and chemical metabolism, cofactor binding interactions are incompletely understood, as is the molecular basis for preferential glucuronidation by UGT1 and UGT2 family enzymes. The study demonstrated that long timescale molecular dynamics (MD) simulations with a UGT2B7 homology model can be used to identify critical binding interactions of a UGT protein with UDP-sugar cofactors. Further, the data provide a basis for the application of MD simulations to the elucidation of UGT–aglycone interactions.

Footnotes

    • Received June 29, 2020.
    • Accepted September 17, 2020.
  • ↵1 P.C.N. and N.C. are joint first authors.

  • This study was supported by the National Health and Medical Research Council of Australia [Grant 1120137]. This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government. R.A.M. is a Beat Cancer Professorial Fellow supported by Cancer Council South Australia (SA) and SA Health.

  • https://doi.org/10.1124/molpharm.120.000104.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 98 (6)
Molecular Pharmacology
Vol. 98, Issue 6
1 Dec 2020
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Research ArticleArticle

Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity

Pramod C. Nair, Nuy Chau, Ross A. McKinnon and John O. Miners
Molecular Pharmacology December 1, 2020, 98 (6) 710-718; DOI: https://doi.org/10.1124/molpharm.120.000104

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Research ArticleArticle

Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity

Pramod C. Nair, Nuy Chau, Ross A. McKinnon and John O. Miners
Molecular Pharmacology December 1, 2020, 98 (6) 710-718; DOI: https://doi.org/10.1124/molpharm.120.000104
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