Structural and functional studies of UDP-glucuronosyltransferases

Anna Radominska-Pandya, Piotr J. Czernik, Joanna M. Little, Eric Battaglia, Peter I. Mackenzie

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    414 Citations (Scopus)

    Abstract

    UDP-Glucuronosyltransferases (UGTs) are glycoproteins localized in the endoplasmic reticulum (ER) which catalyze the conjugation of a broad variety of lipophilic aglycon substrates with glucuronic acid using UDP-glucuronic acid (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 structure and topology are presented, including a dynamic topological model of UGTs in the ER. Evidence from experiments on UGT interactions with inhibitors directed at specific amino acids, photoaffinity labeling, and analysis of amino acid alignments suggest that UDP-GIcUA interacts with residues in both the N- and C-terminal domains, whereas aglycon binding sites are localized in the N-terminal domain. The amino acids identified so far as crucial for substrate binding and catalysis are arginine, lysine, histidine, proline, and residues containing carboxylic acid. Site-directed mutagenesis experiments are critical for unambiguous identification of the active-site architecture.

    Original languageEnglish
    Pages (from-to)817-899
    Number of pages83
    JournalDrug Metabolism Reviews
    Volume31
    Issue number4
    DOIs
    Publication statusPublished - Nov 1999

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