Decarboxylation of uroporphyrinogen I and III in 2,3,7,8-tetrachlorodibenzo-p-dioxin induced porphyria in mice.
The decarboxylation of uroporphyrinogens I and III by porphyrinogen carboxy-lyase (EC 4.1.1.37) in mouse liver supernatant was compared in relation to substrate concentrations. In this species uroporphyrinogen III was the best substrate judging by the criteria of Km/Vmax (estimated for total porphyrinogens) and was converted into coproporphyrinogen faster than its series I isomer. The difference between the two isomers was mainly due to the first decarboxylation. This difference was confirmed by calculation of the Hill coefficient and of Lineweaver-Burk plot which suggested that isomer I induced negative cooperativity in the active centre of the enzyme. After treatment with a porphyrogenic dose of TCDD (25 micrograms/kg/week for 9 weeks) differences between uroporphyrinogen I and III as substrate were maintained. In addition treatment reduced Vmax and Km (estimated for total porphyrinogens) of liver porphyrinogen carboxy-lyase to about half control values for both isomers. Vmax was reduced mainly because of the formation of smaller amounts of all products of decarboxylation, and Km because more heptaporphyrinogen was formed than coproporphyrinogen. Values of the Hill coefficient and Lineweaver-Burk plots suggested TCDD induced altered substrate affinity for isomer III too. Treatment with TCDD did not affect the decarboxylation of uroporphyrinogen III by RBC porphyrinogen carboxy-lyase, estimated from Km and Vmax for total porphyrinogens formed.
D000818:Animals; D002262:Carboxy-Lyases / Q000032:analysis; D003653:Decarboxylation; D004147:Dioxins / Q000633:toxicity*; D004912:Erythrocytes / Q000201:enzymology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011164:Porphyrias / Q000139:chemically induced / Q000378:metabolism*; D011165:Porphyrinogens / Q000378:metabolism*; D014577:Uroporphyrinogens / Q000378:metabolism*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D011165:Porphyrinogens; D014577:Uroporphyrinogens; D002262:Carboxy-Lyases; C022430:porphyrinogen carboxy-lyase