Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt.
We evaluated the erythrocytes of two patients with hereditary pyrimidine 5'-nucleotidase deficiency. Significant findings included an increased reduced glutathione content, increased incubated Heinz body formation, a positive ascorbate cyanide test, and decreased intraerythrocytic pH. The pentose phosphate shunt activity of the patients' red cells as measured by the release of 14CO2 from 14C-1-glucose was decreased compared to high reticulocyte controls. Glucose-6-phosphate dehydrogenase (G6PD) activity in hemolysates from control erythrocytes was inhibited 43% by 5.5 mM cytidine 5'-triphosphate (CTP) and 50% by 5.5 mM in uridine 5'-triphosphate (UTP) at pH 7.1. CTP was a competitive inhibitor for G6P (Ki = 1.7 mM) and a noncompetitive inhibitor for NADP+ (Ki = 7.8 mM). Glutathione peroxidase, glutathione reductase, and 6-phosphogluconate dehydrogenase were not affected by these compounds. Pentose phosphate shunt activity in control red cell hemolysate at pH 7.1 was inhibited to a similar degree by 5.5 mM CTP or UTP. Since the intracellular concentrations of G6P and NADP+ are below their KmS for G6PD, these data suggest that high concentrations of pyrimidine 5'-nucleotides depress pentose phosphate shunt activity in pyrimidin 5'-nucleotidase deficiency. Thus, this impairment of the pentose phosphate pathway appears to contribute to the pathogenesis of hemolysis in pyrimidine 5'-nucleotidase deficiency hemolytic anemia.
D015720:5'-Nucleotidase; D000743:Anemia, Hemolytic / Q000209:etiology*; D002675:Child, Preschool; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000097:blood; D006366:Heinz Bodies; D006801:Humans; D008875:Middle Aged; D009708:Nucleotidases / Q000172:deficiency*; D010428:Pentosephosphates / Q000378:metabolism*; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics; D011742:Pyrimidine Nucleotides / Q000494:pharmacology
D010428:Pentosephosphates; D011742:Pyrimidine Nucleotides; D005954:Glucosephosphate Dehydrogenase; D009708:Nucleotidases; D015720:5'-Nucleotidase; D005978:Glutathione