HEMOLYTIC-ANEMIA IN HEREDITARY PYRIMIDINE 5'-NUCLEOTIDASE DEFICIENCY - NUCLEOTIDE INHIBITION OF G6PD AND THE PENTOSE-PHOSPHATE SHUNT

  • 1 January 1982
    • journal article
    • research article
    • Vol. 60  (5) , 1212-1218
Abstract
The erythrocytes of 2 patients with hereditary pyrimidine 5''-nucleotidase deficiency were evaluated. 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 CTP and 50% by 5.5 mM UTP at pH 7.1 CTP was a competitive inhibitor for G-6-P (Ki [inhibitory constant] = 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 UPT. Since the intracellular concentrations of G6PD and NADP+ are below their Km for G6PD, high concentrations of pyrimidine 5''-nucleotides depress pentose phosphate shunt activity in pyrimidine 5''-nucleotidase deficiency. This impairment of the pentose phosphate pathway appears to contribute to the pathogenesis of hemolysis in pyrimidine 5''-nucleotidase deficiency hemolytic anemia.