Fox R M, Wood M H, O'Sullivan W J
J Clin Invest. 1971 May;50(5):1050-60. doi: 10.1172/JCI106576.
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.
在人红细胞中已证实了从头嘧啶生物合成途径中两种连续酶活性之间的一种协同关系。这两种酶，乳清酸磷酸核糖基转移酶和脱羧酶负责将乳清酸转化为尿苷-5'-单磷酸。根据细胞年龄增加时比重的增加对红细胞进行分级分离，结果显示这两种酶在衰老红细胞中具有显著但相同程度的不稳定性。据推测，乳清酸磷酸核糖基转移酶和脱羧酶形成一种酶-酶复合物，并且遗传性乳清酸尿症中这两种酶的相继缺乏可能反映了该复合物的结构异常。在接受别嘌呤醇治疗的患者中，两种酶的活性协同增加，并且这种增加似乎至少部分是由于衰老红细胞中乳清酸磷酸核糖基转移酶和脱羧酶的稳定。别嘌呤醇核糖核苷酸是乳清苷-5'-单磷酸脱羧酶的体外抑制剂，其合成需要次黄嘌呤鸟嘌呤磷酸核糖基转移酶。然而，对缺乏这种酶的患者给予别嘌呤醇会导致乳清苷尿，并且这些患者红细胞中乳清酸磷酸核糖基转移酶和脱羧酶的活性升高。有证据表明，别嘌呤醇的主要代谢产物氧嘌呤醇，具有一个2,4-二酮嘧啶环，能够作为乳清酸的类似物起作用。据推测，在给予别嘌呤醇后，由乳清酸磷酸核糖基转移酶催化在体内形成氧嘌呤醇核糖核苷酸，会导致乳清苷-5'-单磷酸脱羧酶受到抑制。这种抑制导致过量的乳清苷和乳清酸经尿液排泄，以及乳清酸磷酸核糖基转移酶和脱羧酶的“假底物”稳定化。
