Identification of hydroxywarfarin binding site in human UDP glucuronosyltransferase 1a10: phenylalanine90 is crucial for the glucuronidation of 6- and 7-hydroxywarfarin but not 8-hydroxywarfarin.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Grover P MillerAnna Radominska-Pandya

Abstract

Recent studies show that the extrahepatic human UDP-glucuronosyltransferase (UGT)1A10 is capable of phase II glucuronidation of several major cytochrome P450 metabolites of warfarin (i.e., 6-, 7-, and 8-hydroxywarfarin). This study expands on this finding by testing the hypothesis that the UGT1A10 F(90)-M(91)-V(92)-F(93) amino acid motif is important for proper recognition and conjugation of hydroxywarfarin derivatives. Site-directed mutagenesis studies demonstrate that F(90) is critical for 6- and 7-hydroxywarfarin glucuronidation based on the complete loss of enzymatic activity toward these substrates. In contrast, V92A and F93A mutants lead to higher rates of substrate turnover, have minimum changes in K(m) values, and demonstrate substrate inhibition kinetics. A completely different activity profile is observed in the presence of 8-hydroxywarfarin. No change in either activity or affinity is observed with F90A when compared with wild type, whereas F93A and V92A mutants show increases in V(max) (3- and 10-fold, respectively) and minimum changes in K(m). Liquid chromatographytandem mass spectrometry studies show that enzymatic products produced by mutants are identical to wild-type products produced in the presence of 6-, 7-,...Continue Reading

References

Jan 1, 1997·Pharmacology & Therapeutics·L S Kaminsky, Z Y Zhang
Apr 3, 2002·JAMA : the Journal of the American Medical Association·Mitchell K HigashiAllan E Rettie
Aug 16, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tiia KuuranneRisto Kostiainen
Jan 16, 2007·Archives of Biochemistry and Biophysics·Samuel L CollomGrover P Miller
Oct 9, 2007·The Journal of Pharmacology and Experimental Therapeutics·Agnieszka ZielinskaJeffery H Moran

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Citations

May 5, 2009·Chemical Research in Toxicology·Grover P MillerJeffery H Moran
Oct 6, 2011·The Journal of Pharmacology and Experimental Therapeutics·Stacie M BrattonAnna Radominska-Pandya
Oct 1, 2009·Drug Metabolism Reviews·Drew R JonesGrover P Miller
Apr 13, 2011·Expert Opinion on Drug Metabolism & Toxicology·Drew R Jones, Grover P Miller
Mar 6, 2012·Journal of Pharmaceutical Sciences·Dong Dong, Baojian Wu
Oct 16, 2016·Drug Metabolism and Personalized Therapy·Isabel LópezCristina Belén García

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