Tetrapyrroles as substrates and inhibitors of porphyrinogen carboxy - lyase from rat liver.
Porphyrinogen carboxy-lyase is an enzyme of the haem pathway which catalyses the stepwise decarboxylation of porphyrinogens with different number of carboxyl groups. This enzyme has a low substrate specificity since at least eighteen porphyrinogens were proved to be decarboxylated by the enzyme. In order to clarify this complex process of decarboxylation, studies were carried out using a purified enzyme preparation from rat liver. We studied the behavior of the enzyme in the presence of uroporphyrinogens I, II, III, and IV. The effect of different porphyrins, porphyrinogens and haemin on uroprophyrinogen decarboxylation was also studied to see the influence of nature and position of the side chains of pyrroles as well as the oxidation state in the tetrapyrrolic ring. The liver enzyme decarboxylates the four isomers or uroporphyrinogen. The relative accumulation of intermediates porphyrinogens formed was different from that of isomer III. Uroporphyrinogen IV is an efficient substrate for the porphyrinogen carboxyl-lyase since it was decarboxylated at higher rate than the normal uroporphyrinogen III. The elimination of a carboxyl group of an acetic acid residue located between an acetic and a propionic acid side chain appears to be easier than the one corresponding to an acetic between two propionics or between a methyl and a propionic acid residue. The presence of vicinal propionic side chains in the position 6 and 7 of the reduced porphyrin ring is an important, but not essential requirement for the binding of the enzyme to porphyrinogen. It was found that coproporphyrinogen III inhibits markedly uroporphyrinogen decarboxylation and that haemin also has inhibitory effect on this reaction. The results of the inhibitory studies suggest one or both of the propionic acid residues located in positions 2 and 4 as important factors in the tetrapyrrole enzyme binding. Some other evidence would indicate that possibly the propionic acid side chain at the position 4 may be particularly important. The reduced state of the tetrapyrrolic ring is essential for the decarboxylation process: thus would allow the side chains to adopt a steric disposition facilitating its binding to the enzyme.
D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D011165:Porphyrinogens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011165:Porphyrinogens; D011758:Pyrroles; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase