Overproduction of Pyrimidine Catabolites
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p346-347
2025-09-03
470
Since the end products of pyrimidine catabolism are highly water soluble, pyrimidine overproduction results in few clinical signs or symptoms. Table 1 lists exceptions. In hyper uricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of β-alanine. Since N5,N10-methylene-tetrahydrofo late is required for thymidylate synthesis, disorders of folate and vitamin B12 metabolism result in deficiencies of TMP.
Table1. Metabolic Disorders of Purine & Pyrimidine Matabolism
Orotic Aciduria
The orotic aciduria that accompanies the Reye syndrome probably is a consequence of the inability of severely damaged mitochondria to utilize carbamoyl phosphate, which then becomes available for cytosolic overproduction of orotic acid. Type I orotic aciduria reflects a deficiency of both orotate phosphoribosyltransferase (EC 2.1.3.3) and orotidylate decarboxylase, EC 4.1.1.23 (reactions ➄ and ➅, Figure 1). The rarer Type II orotic aciduria is due to a deficiency only of orotidylate decarboxylase (reaction ➅, Figure 1).
Fig1. The biosynthetic pathway for pyrimidine nucleotides.
Deficiency of a Urea Cycle Enzyme Results in Excretion of Pyrimidine Precursors
Increased excretion of orotic acid, uracil, and uridine accompanies a deficiency in liver mitochondrial ornithine transcarbamoylase . Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods.
Drugs May Precipitate Orotic Aciduria
Allopurinol , an alternative substrate for orotate phosphoribosyltransferase (reaction ➄, Figure 1), competes with orotic acid. The resulting nucleotide product also inhibits orotidylate decarboxylase (reaction ➅, Figure 1), resulting in orotic aciduria and orotidinuria. 6-Azauridine, following conversion to 6-azauridylate, also competitively inhibits orotidylate decarboxylase (reaction ➅, Figure 1), enhancing excretion of orotic acid and orotidine. Four genes that encode urate transporters have been identified. Two of the encoded proteins are localized to the apical membrane of proximal tubular cells.
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