Glucuronate transferase

Figure 32-14. Conjugation of bilirubin with glucuronic acid. The glucuronate donor, UDP-glucuronic acid, is formed from UDP-glucose as depicted. The UDP-glucuronosyl-transferase is also called bilirubin-UGT.

Glucuronidation involves the transfer of D-glucuronic acid from UDP-a-glu-curonic acid to an acceptor compound. The family of enzymes which catalyze this reaction are the UDP-glucuronyl transferases [16]. The reaction proceeds by nucleophilic Sn2 substitution of the C-1 carbon of glucuronic acid, the product undergoing inversion of configuration. The mechanism is illustrated schematically in Figure 7.21. 

GLUCOSE TRACER KINETICS Glucosylceramide j8-D-glucosidase, GLUCOCEREBROSIDASE GLUCURONATE-1-PHOSPHATE URIDYLYL-TRANSFERASE... 

When appreciable cation-independent transferase activities were found (F3, HIO), double reciprocal plots of enzyme activity against concentration of added Mg + were nonlinear, but became linear when only the stimulated enzyme fractions were plotted. The apparent values so obtained were independent of the concentration of UDP-glucuronic acid, and vice versa (HIO), suggesting that Km for Mg + represents the dissociation constant of an Mg +-enzyme complex (D5). 

Conjugation of a drug with glucuronic acid via the glucuronosyl transferases will result in all of the following EXCEPT... 

Fig. (15). Metabolism of dietary flavonoids. GlcA = glucuronic acid UGT - uridine 5 -diphospoglucuronosyl transferase Met = methyl Sulf = sulfate COMT = catechol-O-methyl transferase PST = phenol sulfo transferase...

Conjugation involves addition of an endogenous moiety to a foreign molecule, which may be a product of a phase 1 reaction. Major phase 2 routes conjugation with glucuronic acid, sulfate, glutathione amino acids acetylation methylation. Enzymes involved are transferases except in the case of amino acid conjugation where the first step is catalyzed by an acyl CoA synthetase, then a transferase is involved. 

The mouse has less sulfotransferase activity with respect to the a-hydroxytamoxifen, but more glucuronosyl transferase activity. The resulting glucuronic acid conjugation is a clear detoxication pathway, as a stable metabolite is formed, which can be readily eliminated. Hence, the mouse is much less susceptible, and although some tamoxifen is covalently bound to liver DNA, no hepatic tumors have been detected. 

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