Defective function of a microsomal UDP-glucuronyltransferase in Gunn rats.
The kinetic parameters of the p-nitrophenol-metabolizing form of UDP-glucuronyltransferase [-UDPglucuronosyltransferase; UDPglucuronate beta-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] have been compared in liver microsomes from the Gunn strain of rat and from normal; Wistar rats. The abnormally low rate of glucuronidation of p-nitrophenol in the Gunn rats, as compared with Wistar rats, is due to decreased affinity of UDP-glucuronyltransferase for UDP-glucuronic acid. Activities at Vmax and the Michaelis constant for p-nitrophenol, KPNP, of UDP-glucuronyltransferase are the same for enzyme from either strain of rat. Studies of the kinetic parameters of the reverse reaction catalyzed by UDP-glucuronyltransferase indicate that the enzyme from Gunn rats also has decreased affinity for UDP. Calculated values of deltaG degrees for the binding of the UDP portion of UDP-glucuronic acid suggest that the defect of UDP-glucuronyltransferase of Gunn rats appears limited to abnormal interactions between the enzyme and the UDP portion of UDP-glucuronic acid. Studies of the extent of UDP-induced inhibition of the forward reaction support this idea. Diethylnitrosamine, added to microsomes in vitro, enhances the affinity of UDP-glucuronyltransferase for the UDP portion of UDP-glucuronic acid. Despite the defective conformation of the UDP-glucuronic acid binding site of UDP-glucuronyltransferase from Gunn rats this enzyme is activated in the normal way by UDP-N-acetylglucosamine, which is a K-type effector with regard to UDP-glucuronic acid.
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D014453:Glucuronosyltransferase / Q000172:deficiency* / Q000378:metabolism; D006602:Hexosyltransferases / Q000172:deficiency*; D006720:Homozygote; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009596:Nitrophenols / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology; D051381:Rats / Q000378:metabolism*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000494:pharmacology
D009596:Nitrophenols; D009602:Nitrosamines; D014535:Uridine Diphosphate Glucuronic Acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D006602:Hexosyltransferases; D014453:Glucuronosyltransferase