UDP-Glucuronosyl Transferases

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Introduction
Chemistry
Enzymology
Drug Metabolism
Clinical Aspects
References

Introduction

Glucuronidation is the major pathway in phase II metabolism and accounts for approximately 35% of drug conjugation. The reaction is the chemical binding of a substance to glucuronic acid, via a glycosidic bond. The product, a glucuronide conjugate, has enhanced water solubility, aiding elimination from the body.

In mammals, glucuronic acid is the main sugar used to prevent the accumulation of waste products from metabolism and other fat-soluble chemicals (endogenous and exogenous).

The wide occurance of glucuronidation is probably a result of the co-factor, UDG-glucuronic acid, being a key factor in intermediary metabolism and the close relationship with glycogen synthesis. The scale of glucuronidation in the body is emphasised by its numerous roles in the excretion of both exogenous and endogenous substances.

Endogenous substrates include:

  • steroids
    • androgens
    • oestrogens
    • progestins
    • corticosteroids
  • bile acids
  • bilirubin
  • retinoids
  • fatty acids

Conjugation with glucuronic acid is catalysed by uridine di-phosphate (UDP)- glucuronosyl transferases – microsomal membrane bound proteins. The enzyme catalyses the transfer of a glucuronate group of urindine diphosphoglucuronate (UDPGA – a co-substrate) to the functional group of specific substrates (noted in the table above). In general, functional groups acted on include hydroxyl, carboxylate, amino and sulfate groups, many of which may have been formed as part of Phase 1 metabolism.