Structural and functional studies of UDP-glucuronosyltransferases

UDP-Glucuronosyltransferases (UGTs) are glycoproteins localized in the endo plasmic reticulum (ER) which catalyze the conjugation of a broad variety of lipophilic aglycon substrates with glucuronic acid using UDP-glucuronic ac id (UDP-GIcUA) as the sugar donor. Glucuronidation is a major factor in the elimination of lipophilic compounds from the body. In this review, current information on the substrate specificities of UGT1A and 2B family isoforms is discussed. Recent findings with regard to UGT st ructure and topology are presented, including a dynamic topological model o f UGTs in the ER. Evidence from experiments on UGT interactions with inhibitors directed at s pecific amino acids, photoaffinity labeling, and analysis of amino acid ali gnments suggest that UDP-GIcUA interacts with residues in both the N- and C -terminal domains, whereas aglycon binding sites are localized in the N-ter minal domain. The amino acids identified so far as crucial for substrate binding and cata lysis are arginine, lysine, histidine, proline, and residues containing car boxylic acid. Site-directed mutagenesis experiments are critical for unambi guous identification of the active-site architecture.