Mechanism and multiplicity of UDPglucuronyltransferases

Glucuronidation consists in a molecule of glucuronic acid being transferred from the cofactor uridine-5'-diphospho-a-D-glucuronic acid (39, Figure 15; UDPGA) to the substrate. This cofactor is produced endogenously by C6 oxidation of UDP-a-D-glucose, and it is recognized that about 5 g are synthesized daily in the adult human body, hence the high capacity of this metabolic route.

Glucuronic acid exists in UDPGA in the 1a-configuration, but the products of conjugation are b-glucuronides (40, Figure 15). This is due to the mechanism of the reaction being a nucleophilic substitution with inversion of configuration. Indeed, all functional groups able to undergo glucuronidation are nucleophiles, a common characteristic they share despite their great chemical variety. As a consequence of this diversity, the products of glucuronidation are classified as O-, N-, S-, and C-glucuronides. Practically all functional groups that are glucuronidated are shown in Figure 15. The hydroxy groups (phenols, alcohols, carboxylic acids, carbamic acids, hydroxylamines, and hydroxylamides) form O-glucuronides and are grouped in Figure 15a together with strongly acidic enolic acids, a very few of which are known to form C-glucuronides. The N-glucuronides are grouped in Figure 15b and are generated from amides, sulfonamides, aromatic amines, heterocyclic amines, and aliphatic amines; also shown in Figure 15b are the thiols, which lead to S-glucuronides.

The enzymes catalyzing these highly diverse reactions are known as UDP-glucuronyltransferases (UDP-glucuronosyltransferases; EC 2.4.1.17; UDPGT) and consist in a number of proteins coded by genes of the UGT superfamily (Table 3). The human UDPGT known to metabolize xenobiotics are the products of two gene families, UGT1 and UGT2. Their major substrates classes are also summarized in Table 3.72-78

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