The crystal structure of human UDP-glucuronosyltransferase 2B7 C-terminal end is the first mammalian UGT target to be revealed: the significance for human UGTs from both the 1A and 2B families

Abstract

Human UDP-glucuronosyltransferases (EC 2.4.1.17) (UGTs) are major phase II metabolism enzymes that detoxify a multitude of endo- and xenobiotics through the covalent addition of a glucuronic acid moiety. UGTs are promiscuous enzymes that regulate the levels of numerous important endobiotics in a range of tissues, and inactivate most therapeutic compounds in concert with phase I enzymes. In spite of the importance of these enzymes, we have only a limited understanding of the molecular mechanisms governing their substrate specificity and catalytic activity. Until recently, no three-dimensional structural information was available for any mammalian UGT. The 1.8-å resolution apo crystal structure of the UDP-glucuronic acid binding domain of human UGT2B7 (2B7CT) is the only structure of a mammalian UGT target determined to date. In this review, we summarize what has been learned about human UGT function from the analysis of this and other related glycosyltransferase (GT) crystal structures.

Keywords::

• Homology modeling
• metal dependence
• binding site
• catalytic mechanism
• contact residues

Acknowledgments

The authors would like to acknowledge the scientific efforts of Agnieszka K. Zielinska, Yan Xiong, Jeffrey E. Keenan, Anne-Sisko Patana, and Moshe Finel in the generation of the data for this review. Moreover, they would like to thank Joanna Little for the final editing of this review.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.