S-Glucuronidation of 7-mercapto-4-methylcoumarin by human UDP glycosyltransferases in genetically engineered fission yeast cells

Author:

Buchheit Daniela,Schmitt Ellen I.,Bischoff Daniel,Ebner Thomas,Bureik Matthias

Abstract

AbstractHuman UDP glycosyltransferases (UGTs) play an important role in xenobiotic detoxification. They increase the solubility of their substrates by adding a sugar moiety (such as glucuronic acid) to different functional entities (such as hydroxyl groups). The aim of this study was to investigate how glucuronidation of a standard substrate is affected by a change of the hetero­atom at the conjugation site. For this purpose, we compared thein vitroglucuronidation rates of 4-methylumbelliferone and 7-mercapto-4-methylcoumarin, respectively. Human liver microsomes catalyzed theS-glucuronidation of 7-mercapto-4-­methylcoumarin almost as efficient as theO-glucuronidation of 4-methylumbelliferone. When testing isoenzyme specificity by whole cell biotransformation with fission yeast strains that recombinantly express all 19 human members of the UGT1 and UGT2 families, it was found that 13 isoenzymes were able to glucuronidate 7-mercapto-4-methylcoumarin, with five of them being specific for this substrate and the other eight also converting 4-methylumbelliferone under these conditions. The remaining six UGTs did not accept either substrate. Out of the eight isoenzymes that glucuronidated both substrates, four catalyzed both reactions approximately to the same extent, while three displayed higher conversion rates towards 4-methylumbelliferone and one preferred 7-mercapto-4-methylcoumarin. These data suggest that 7-mercapto-4-methylcoumarin is a convenient new standard substrate for monitoringS-glucuronidation.

Publisher

Walter de Gruyter GmbH

Subject

Clinical Biochemistry,Molecular Biology,Biochemistry

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