UDP-Glycosyltransferases

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

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 (SN<2) 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.

Original languageEnglish
Title of host publicationComprehensive Toxicology
Subtitle of host publicationThe Curated Reference Collection in Biomedical Sciences
PublisherScience Direct
Pages468-496
Number of pages29
Volume10
Edition3rd
ISBN (Electronic)9780081006122
ISBN (Print)9780128012383
DOIs
Publication statusPublished - 2018

Bibliographical note

'Change History: May 2017. R Meech updated the text and further readings to this entire article, replaced Figure 2 with an updated version, and added new Figure 5. JO Miners updated section 4.20.6. DG Hu, JO Miners, and PI Mackenzie reviewed the entire revised article and made corrections where appropriate.

This is an update of Mackenzie, P.I., Gardner-Stephen, D.A., Miners, J.O., UDP-Glucuronosyltransferases, Comprehensive Toxicology, Second Edition, edited by Charlene A. McQueen, Elsevier, Oxford, 2010, Volume 4, Pages 413–434.'

Keywords

  • UDP-glycosyltransferases
  • Glycosidation
  • Metabolism
  • Gene regulation
  • Glucuronidation
  • Oligomerization

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  • Cite this

    Meech, R., Hu, D-G., Miners, J. O., & Mackenzie, P. I. (2018). UDP-Glycosyltransferases. In Comprehensive Toxicology: The Curated Reference Collection in Biomedical Sciences (3rd ed., Vol. 10, pp. 468-496). Science Direct. https://doi.org/10.1016/B978-0-12-801238-3.65733-1