Understanding substrate selectivity of human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes

Abstract

The UDP-glucuronosyltransferase (UGT) enzyme catalyzes the glucuronidation reaction which is a major metabolic and detoxification pathway in humans. Understanding the mechanisms for substrate recognition by UGT assumes great importance in an attempt to predict its contribution to xenobiotic/drug disposition in vivo. Spurred on by this interest, 2D/3D-quantitative structure activity relationships (QSAR) and pharmacophore models have been established in the absence of a complete mammalian UGT crystal structure. This review discusses the recent progress in modeling human UGT substrates including those with multiple sites of glucuronidation. A better understanding of UGT active site contributing to substrate selectivity (and regioselectivity) from the homologous enzymes (i.e., plant and bacterial UGTs, all belong to family 1 of glycosyltransferase (GT1)) is also highlighted, as these enzymes share a common catalytic mechanism and/or overlapping substrate selectivity.

Identification of Flavone Glucuronide Isomers by Metal Complexation and Tandem Mass Spectrometry: Regioselectivity of Uridine 5′-Diphosphate–Glucuronosyltransferase Isozymes in the Biotransformation of Flavones

“…The activities of UGT enzymes were previously assessed in the presence of organic solvents at various concentrations, and it was reported that there were no significant changes in enzyme activities for solutions containing up to 2% methanol content. 43 Thus, the use of a minor portion of methanol (~1.25% of total volume of solution) in the present study was not expected to be a major detriment to enzymatic activity. 46 This low concentration of methanol enhanced the solubility of the flavones and led to more accurate concentrations in solution.…”

“…42 There has also been considerable progress in modeling human UDP-glucuronsyltransferase quantitative structure/activity relationships (QSAR) and prediction of regioselectivity, as summarized in a recent review. 43 This type of QSAR modeling has already begun to shed light on understanding the complex substrate selectivity of human UGTs. 43 …”

“…43 This type of QSAR modeling has already begun to shed light on understanding the complex substrate selectivity of human UGTs. 43 …”

Differences in the Glucuronidation of Resveratrol and Pterostilbene: Altered Enzyme Specificity and Potential Gender Differences

“…Answers to these questions will hopefully be available as UGT/substrate prediction modeling continues to mature. 28,29) …”

Enzymatic Detoxication, Conformational Selection, and the Role of Molten Globule Active Sites

“…For example, the biological function of detoxication enzymes, such as cytochrome P450s (10), UDPglucuronosyl transferases (11), glutathione transferases (GSTs) (12,13) and others, includes their ability to bind and metabolize an extraordinary range of chemically diverse substrates, and hence they control the elimination of most clinically used drugs and environmental toxins (10). Such enzymes contribute to many clinically defined drug-drug interactions (14).…”