Regioselective Sulfation and Glucuronidation of Phenolics: Insights into the Structural Basis

Baojian      Wu; Sumit      Basu; Shengnan      Meng; Xiaoqiang      Wang; Ming      Hu

Abstract

The phase II metabolism sulfation and glucuronidation, mediated by sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) respectively, are significant metabolic pathways for numerous endo-and xenobiotics. Understanding of SULT/UGT substrate specificity including regioselectivity (i.e., position preference) is of great importance in predicting contribution of sulfation/ glucuronidation to drug and metabolite disposition in vivo. This review summarizes regioselective sulfation and glucuronidation of phenolic compounds with multiple hydroxyl (OH) groups as the potential conjugation sites. The strict regioselective patterns are highlighted for several SULT and UGT isoforms towards flavonoids, a large class of natural polyphenols. To seek for a molecular-level explanation, the enzyme structures (i.e., SULT crystal structures and a homology-modeled UGT structure) combined with molecular docking are employed. In particular, the structural basis for regioselective metabolism of flavonoids by SULT1A3 and UGT1A1 is discussed. It is concluded that the regioselective nature of these phase II enzymes is determined by the size and shape of the binding pocket. While the molecular structures of the enzymes can be used to explain regioselective metabolism regarding the binding property, predicting the turnover at different positions remains a particularly difficult task.

Keywords: Phenolics, flavonoids, phase II metabolism, sulfation, glucuronidation, SULTs, UGTs, homology modeling, Flavopiridol, regioselectivity