Studies on the coordinate activity and liability of orotidylate phosphoribosyltransferase and decarboxylase in human erythrocytes, and the effects of allopurinol administration.
A coordinate relationship between the activities of two sequential enzymes in the de novo pyrimidine biosynthetic pathway has been demonstrated in human red cells. The two enzymes, orotidylate phosphoribosyltransferase and decarboxylase are responsible for the conversion of orotic acid to uridine-5'-monophosphate. Fractionation of red cells, on the basis of increase of specific gravity with cell age, has revealed that these two enzymes have a marked but equal degree of lability in the ageing red cell. It is postulated that orotidylate phosphoribosyltransferase and decarboxylase form an enzyme-enzyme complex, and that the sequential deficiency of these two enzymes in hereditary orotic aciduria may reflect a structural abnormality in this complex. In patients receiving allopurinol, the activities of both enzymes are coordinately increased, and this increase appears to be due, at least in part, to stabilization of both orotidylate phosphoribosyltransferase and decarboxylase in the ageing red cell. Allopurinol ribonucleotide is an in vitro inhibitor of orotidine-5'-monophosphate decarboxylase and requires the enzyme hypoxanthineguanine phosphoribosyltransferase for its synthesis. However, the administration of allopurinol to patients lacking this enzyme results in orotidinuria and these patients have elevated orotidylate phosphoribosyltransferase and decarboxylase activities in their erythrocytes. Evidence is presented that the chief metabolite of allopurinol, oxipurinol, with a 2,4-diketo pyrimidine ring is capable of acting as an analogue of orotic acid. It is postulated that the in vivo formation of oxipurinol ribonucleotide, catalyzed by orotidylate phosphoribosyltransferase, after allopurinol administration, leads to inhibition of orotidine-5'-monophosphate decarboxylase. This inhibition results in the urinary excretion of excessive amounts of orotidine and orotic acid, and "pseudo-substrate" stabilization of orotidylate phosphoribosyltransferase and decarboxylase.
D000225:Adenine / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D002247:Carbon Isotopes; D002262:Carboxy-Lyases / Q000378:metabolism*; D002499:Centrifugation, Density Gradient; D003864:Depression, Chemical; D004912:Erythrocytes / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007042:Hypoxanthines / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000188:drug therapy / Q000378:metabolism; D009705:Nucleosides / Q000652:urine; D009963:Orotic Acid / Q000652:urine; D014166:Transferases / Q000378:metabolism*; D014500:Uracil Nucleotides / Q000096:biosynthesis
D002247:Carbon Isotopes; D007042:Hypoxanthines; D009705:Nucleosides; D014500:Uracil Nucleotides; D009963:Orotic Acid; D000493:Allopurinol; D014166:Transferases; D002262:Carboxy-Lyases; D000225:Adenine