Insights on membrane topology and structure/function of UDP-glucuronosyltransferases

Abstract

The main characteristic of uridine diphosphate (UDP)-glucuronosyltransferases is their potency to glucuronidate a large array of structurally unrelated substances with various nucleophilic groups. The activity of these enzymes strongly depends on their tight association to the membrane of the endoplasmic reticulum. In light of recent data, this review is focused on the membrane-assembly process, which is a prerequisite for activity, and on the amino acids that govern substrate recognition and catalysis at the active site. The major implication of the highly variable N-terminal domain of UDP-glucuronosyltransferases in the substrate specificity of these enzymes is highlighted. In the absence of crystal data of the N-terminal domain, multidisciplinary approaches of genetic-/protein-engineering techniques, homology modeling with glycosyltransferases, and quantitative structure-activity relationships allowed us to point out crucial amino acids. On the basis of these results, possible reaction mechanisms for the glucuronidation of xenobiotics, involving histidine and aspartic acid residues, have been built and are discussed.

Keywords::

• Substrate specificity
• substrate plasticity
• membrane topology
• reaction mechanism
• drug glucuronidation

Acknowledgements

This work was supported by the Région Lorraine, the Conseil Général 54, and the ANR-08-BLAN-0163-01 and ANR-08-PCVI-0023-01.

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