Pyrimidine metabolism abnormalities

The number of inherited defects of the pyrimidine metabolism described so far is small, compared to that of the purine metabolism. Combined deficiency of orotate phosphoribosyltransferase (OPRT) (EC 2.4.2.10) and orotidine 5 -monophosphate decarboxylase (ODC) (EC 4.1.1.23), designated as type I hereditary orotic aciduria, presents with characteristic clinical features such as hypochromic anemia with a megaloblastic bone marrow and crystalluria. Only six patients have been described and, as far as we know, new cases have not been discovered recently. ODC deficiency with similar clinical phenomena and leading to increased urinary excretion of orotate and orotidine has been detected in only one patient (1). A third defect, a deficiency of pyrimidine 5 -nucleotidase (Py-5NX (EC 3.1.3.5.) in erythrocytes, is associated with chronic hemolytic anemia and prominent basophylic stippling of the erythrocytes due to accumulated pyrimidine nucleotides. An increasing number of patients have been reported, their detection being facilitated by the typical phenomena. We do not know whether the urinary pyrimidine profile in this condition is abnormal. 

A.H. van Gennip, E.J. van Bree-Blom, S.K. Wadman, M. Duran and F.A. Beemer, HPLC of urinary pyrimidines for the evaluation of primary and secondary abnormalities of pyrimidine metabolism, in "Biological/biomedical Applications of Liquid Chromatography III, ed. G.L. Hawk, Marcel Dekker, Inc. New York and Basel (1982), pp 285-296. 

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Allopurinol and oxipurinol inhibit pyrimidine biosynthesis de novo by establishing a metabolic block which results in orotic aciduria and orotidinuria. This block appears to be due to inhibition of ODC by one or more of at least four ribonucleotide derivatives 1-allopurinol ribonucleotide, 1-oxipurinol ribonucleotide, 7-oxipurinol ribonucleotide and xanthosine-5 -monophosphate. However, to date the interference has not produced any recognized, clinically significant abnormalities. 

Both of these activities contrast, though not necessarily conflict, with the findings in adult and newborn mice that 70% of A -hydroxy-[ C] urethane is converted in vivo to [ C]urethane. This suggests that urethane is metabolically closer to the ultimate species of the carcinogen than A -hydroxyurethane in the carcinogenicity of both chemicals in mice. One mode of action of urethane or its A -hydroxy metabolite may also be as an antimetabolite in pyrimidine biosynthesis. Boyland and Koller found that the frequency of chromosome abnormalities induced by urethane (but not nitrogen... 

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