Glucuronidation is an important pathway in the biotransformation and excretion of exogenous drugs and other xenobiotics and endogenous compounds, such as bilirubin, steroid hormones, bile and fatty acids, and thyroid hormones. Conjugation with glucuronic acid generally results in the increased solubility and decreased biological activity of a compound. However, glucuronidation may be involved in the bioactivation of compounds to mutagens, carcinogens or other pharmacological active forms. UDP- glucuronosyltransferases (UGTs) are a family of enzymes responsible for glucuronidation. The present proposal focuses on the expression of human UGT cDNA in suitable host cells and characterization of the structure of the cloned protein in the absence of interfering UGTs isoenzyme. One of the principal goals will be to elucidate how the multi-substrate specificity of human UGTs are encoded in their primary and tertiary structure in order to understand the role of glucuronidation in the metabolism of endogenous substrates, drugs, and xenobiotics in humans. The project will be carried out in two laboratories (University of Arkansas and University of Nancy, France) with complementary expertise in the study of human recombinant UGTs. The studies will be applied to the following four recombinant human UGT isoenzyme; two physiologically important UGTs, UGT2B4 (hyodeoxycholic acid-specific and UGT1*1 bilirubin specific), as well as UGT*6 (small, planar phenol- specific and UGT2B10, a novel UGT of unknown substrate specificity. There are two complementary goals: (1) to synthesize human recombinant UGTs in amounts sufficient to characterize, purify, produce antibodies nd for structural studies; (2) to study the structure of human recombinant UGTs and their relationship to the functional properties of the individual isoforms.
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