Insight into the structure, oligomerization, and the role in drug resistance of human UDP-glucuronosyltransferases.

Abstract

Human UDP-glucuronosyltransferases (UGTs) are pivotal phase II metabolic enzymes facilitating the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to various substrates. UGTs are classic type I transmembrane glycoproteins, mainly localized in the endoplasmic reticulum (ER) membrane. This review comprehensively explores UGTs, encompassing gene expression, functional characteristics, substrate specificity, and metabolic mechanisms. A recent analysis of C-terminal structures, compared with original data, underscores the pivotal role of α3, α4, and β4 functional domains in selectively recognizing diverse glycosyl donors. Accumulating evidence suggests that UGTs function as homo- and heterodimers, with oligomers likely stabilizing UGTs and modulating their activity. The review sheds light on the implications of UGT oligomerization on substrate glucuronidation and the interplay between protein-protein interaction and glucuronidation activity. UGT-mediated drug resistance, often underestimated, emerges as a clinically relevant form of chemical resistance, with delineated outcomes in tumors and other diseases. This review provides a multifaceted exploration of the physiological significance of UGTs, spanning genetics, proteins, oligomerization, drug resistance, and more, offering insights into their metabolic mechanisms. Understanding interactions between UGT isoforms is crucial for predicting drug-drug interactions, preventing drug toxicity, and enabling precision treatment.