STRUCTURE AND FUNCTION OF URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASES

Clinical and Experimental Pharmacology and Physiology - Tập 24 Số 12 - Trang 907-915 - 1997
Robyn Meech1, Peter I. Mackenzie2
1Department of Clinical Pharmacology, Flinders University of South Australia, Australia.
2Department of Clinical Pharmacology, Flinders University of South Australia, Bedford Park, South Australia, Australia.

Tóm tắt

SUMMARY1. The uridine diphosphate (UDP)‐glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine.2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more pola. glucuronide.3. The UGT protein can be conceptually divided into two domains with the amino‐terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a ‘loose’ fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl‐terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA).4. Uridine diphosphat. glucuronosyltransfera.se is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER‐targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate‐binding domains and the catalytic site.5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER‐derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine diphosphate glucuronosyltransfer‐ase activity is also highly lipid dependent and the enzyme may contain regions of membrane association in addition to the transmembrane domain.

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Clinical and Experimental Pharmacology and Physiology

Tập 24 Số 12

907-915

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