BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

SECTION 10. NUCLEOTIDE METABOLISM

VII. Disorders of Pyrimidine Nucleotide Metabolism

Several disorders associated with decreased activity of Enzymes involved in pyrimidine Nucleotide METABOLISM have been described. One of them, orotic aciduria, is caused by a defect In the second bifunctional enzyme of de novo nucleotide synthesis—UMP synthase; two others are identified during pyrimidine Catabolism.

A. Orotic Aciduria

This is the sole disorder of de novo pyrimidine synthesis. It is caused by reduced activity of UMP synthase, which catalyzes the formation and decarboxylation of OMP. Since embryonic development relies on de novo pyrimidine synthesis to supply DNA Synthesis with precursors, fetal survival is impossible in the complete absence of this enzyme's activity. Indeed, all patients with orotic aciduria exhibit measurable, albeit very low, UMP synthase activity. It has been established that the urinary excretion of orotic acid in patients (1 g/day or more) significantly exceeds the normal daily synthesis of orotate (about 600 mg/day). The decreased synthesis of pyrimidine NUCLEOTIDES observed in this pathology impairs the feedback inhibition Regulation of the CAD enzyme, leading to orotate overproduction.

Clinically, the most characteristic consequence of orotic aciduria is megaloblastic anemia, caused by the body's inability to maintain a normal rate of erythroid Cell Division. It is diagnosed in children on the basis that it is refractory to Folic acid therapy.

Deficient synthesis of pyrimidine nucleotides impairs intellectual development and motor function, and is accompanied by cardiac and gastrointestinal disorders. Formation of The Immune System is disrupted, leading to increased susceptibility to various infections.

Orotic acid hyperexcretion is accompanied by Urinary Tract dysfunction and Kidney stone formation. Without Treatment, affected individuals typically do not survive past early childhood. Notably, orotic acid itself is non-toxic; the numerous systemic dysfunctions stem entirely from "pyrimidine starvation."

The treatment for this condition involves administering uridine (0.5 to 1 g/day), which is converted to UMP via a salvage pathway.

Uridine + ATP > UMP + ADP.

Uridine supplementation relieves "pyrimidine starvation," and since all other pyrimidine nucleotides can be synthesized from UMP, orotic acid excretion decreases as the feedback inhibition of the CAD enzyme is restored. For patients with orotic aciduria, uridine therapy must be maintained throughout life, making this nucleoside an essential dietary factor for them.

In addition to genetically determined causes, orotic aciduria may occur:

✵ in hyperammonemia caused by a defect in any of The Urea Cycle enzymes, except for carbamoyl phosphate synthetase I. In this case, carbamoyl phosphate synthesized in the Mitochondria enters The Cell Cytosol and is channeled into pyrimidine nucleotide synthesis. The concentrations of all metabolites, including orotic acid, increase. The most significant orotate excretion is observed in Ornithine transcarbamylase deficiency (the second enzyme of the urea cycle);

✵ during Gout treatment with allopurinol, which is converted to oxypurinol mononucleotide and acts as a potent inhibitor of UMP synthase. This leads to the accumulation of orotic acid in Tissues and Blood.

B. Disorders of Pyrimidine Catabolism

Disorders affecting two enzymes of this metabolic pathway are known.

Deficiency of pyrimidine-5'-nucleotidase disrupts the removal of inorganic phosphate from pyrimidine mononucleotides and The formation of nucleosides.

An inactive isoform of pyrimidine-5'-nucleotidase has been identified in erythrocytes. Consequently, pyrimidine NTPs accumulate, inhibiting the Pentose Phosphate Pathway of glucose metabolism and thereby predisposing erythrocytes to hemolysis (see Section 14).

Dihydropyrimidine dehydrogenase is the rate-limiting enzyme of pyrimidine catabolism. Impairment of this enzyme is accompanied by neurological abnormalities and is diagnosed on The basis of elevated levels of free Pyrimidines—uracil and thymine—in Blood Plasma.