The glycosidation of xenobiotics and endogenous compounds: Versatility and redundancy in the UDP glycosyltransferase superfamily

Abstract

The covalent addition of sugars to small organic molecules is mediated by a superfamily of UDP glycosyltransferases (UGTs) found in animals, plants and bacteria. This superfamily evolved by gene duplication and divergence to manage exposure to a changing environment of lipophilic chemicals. The recent characterization of the UGT3A family provides further insights into the origin and evolution of this superfamily in mammals and the role of individual UGTs in the formation of the various chemical glycosides found in body tissues and fluids. Furthermore, the unique UDP-sugar specificities of the two enzymes in this family inform our knowledge of UGT structure relating to catalysis and UDP-sugar specificity. In addition to the UGT3 gene family, three other gene families, UGTs1, 2, and 8, are found in mammalian genomes. The 19 members of the UGT1 and 2 families have a major role in processing lipophilic chemicals due to their capacity to glucuronidate a broad range of structurally-dissimilar substrates. In contrast, the UGT3 enzymes only have a minor role, as their activities are very low in the major drug-metabolic organs, and their N-acetylglucosaminide and glucoside products are only a minor component of circulating and excreted drug metabolites. Although the endogenous role of the UGT3 family is still unknown, participation in the processing of lipophilic chemicals in specific cell types or at specific times during ontogeny cannot be excluded. In contrast to the UGT 1, 2 and 3 families, the single member of the UGT8 family appears to have no role in drug metabolism.

Introduction

Our capacity to respond to drugs and organic chemicals present in the environment, and to regulate the milieu of chemical ligands in cells, is mediated by multigene families of drug metabolizing enzymes (Mackenzie et al., 2010). Although members of these families display regio- and stereo-selectivity towards chemicals, their broad, overlapping substrate selectivities ensure that few low molecular weight organic compounds escape metabolism. This plasticity is crucial to preventing chemical toxicity and controlling cellular homeostasis. One major family of drug metabolizing enzymes is the UDP glycosyltransferase (UGT) family¹ (Tukey and Strassburg, 2000, Miners et al., 2004, Mackenzie et al., 2005). Members of this family catalyze the covalent attachment of hexose moieties to lipophilic chemicals, thereby altering their biological properties and aiding in their recognition by influx and efflux transporters. The latter changes their distribution in the body and enhances their elimination via the bile or urine. This process of glycosidation² uses activated sugar donors in the form of the uridine diphosphate sugars, UDP-glucuronic acid (UDP-GlcUA), UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal), UDP-xylose (UDP-Xyl) and UDP-N-acetylglucosamine (UDP-GlcNAc), and hydroxyl, carboxyl, thiol, amine and carbonyl functional groups on the chemical as sugar acceptors. Glycosidation, in general, is a strategy for minimizing the accumulation of chemicals to toxic levels in cellular membranes by facilitating their excretion in urine and bile, and specifically, regulating intracellular concentrations of chemical signaling molecules (e.g. steroid hormones and other nuclear receptor ligands). In rare cases, glycosidation of small molecules may be an intermediate step in the synthesis of more complex cellular components, as illustrated by the formation of ceramide galactoside, an intermediate in sphingolipid synthesis (Bosio et al., 1996).

In mammals, the overwhelming role of glucuronidation in the metabolism of a vast array of environmental and dietary chemicals and endogenous products of metabolism, and the importance of the UGT1 and 2 families in this process is well documented (for example, see reviews of (Miners and Mackenzie, 1991, Mackenzie, 1995, Miners et al., 2004). In contrast, the role of glycosidation with other sugars including glucose, xylose, galactose and N-acetylglucosamine in mammals is much less understood. The focus of this review will be the newly discovered human UGT3 family. The members of this family have novel UDP-sugar specificities, however, their contribution to drug metabolism and endogenous metabolism remains largely unknown. This review will provide an overview of the importance of the UGT family from an evolutionary perspective, document the various chemical glycosides other than glucuronides found in human tissues and fluids, and discuss the role and importance of the UGT3A forms and other UGTs in their formation. This review will also describe current structural aspects of the UGT protein relating to catalysis and UDP-sugar specificity and suggest future studies to further clarify the physiological and toxicological roles of the UGT superfamily.