10.20 - UDP-Glycosyltransferases

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The UDP-glycosyltransferase enzyme superfamily (UGT) consists of UDP-glucuronosyltransferases (the UGT1 and 2 families), UDP N-acetylglucosaminyltransferase (UGT3A1), UDP-glucosyl/xylosyltransferase (UGT3A2), and UDP-galactosyltransferase (UGT8) that conjugate glucuronic acid, N-acetylglucosamine, glucose, xylose, and galactose sugars to nucleophilic O, N, S, and C atoms on lipophilic compounds via a nucleophilic bimolecular substitution (SN2) mechanism. The aglycone substrates glycosidated include drugs, environmental chemicals, and endogenous compounds such as bilirubin and steroid hormones. The glycoside products are water-soluble and readily excreted. There are 22 functional human UGTs belonging to four UGT families: UGT1 containing nine members, UGT2 containing seven UGT2B and three UGT2A members, UGT3 containing two members, and UGT8 containing one member. These UGTs reside on the luminal side of the endoplasmic reticulum and consist of two domains, an N-terminal domain involved in substrate selection and catalysis and a C-terminal domain responsible for binding the sugar donor, UDP glucuronic acid, UDP-glucose, UDP-xylose, UDP-N-acetylglucosamine, or UDP-galactose depending on UGT isoform. The UGT protein is integrated into the endoplasmic reticulum membrane by a hydrophobic series of amino acids near the C-terminus and appears to form homo- or heterodimers with other UGT proteins and complexes with other drug-metabolizing enzymes. UGT genes are regulated by several liver-enriched transcription factors (LETFs) such as HNF1 and HNF4α and by ligand-activated transcription factors (TFs) such as AhR, Nrf2, PXR, CAR, PPAR, FXR, LXR, ER, and AR. Regulation by these TFs ensures that each tissue or organ has a distinct complement of UGTs. Several polymorphisms in UGT genes and their regulatory regions have been shown to alter the glycosidation capacity of tissues and organs and to be risk factors for disease and adverse drug events.