Adenosine- and deoxyadenosine-mediated altered pyrimidine metabolism in human adeosine deaminase-deficient...

To evaluate the importance of altered pyrimidine synthesis in the relationship between immune dysfunction and deficiency of ADA, this pathway has been evaluated in normal and ADA-deficient human lymphoblasts. Adenosine and deoxyadenosine effect comparable reductions of radiolabeled bicarbonate incorporation in uridine nucleosides of both normal and deficient cells, with this effect being more prolonged in deficient cells. In ADA-deficient lymphoblasts this altered pyrimidine metabolism is accompanied by reduced intracellular concentrations of PP-ribose-P with adenosine but not deoxyadenosine. The altered PP-ribose-P levels are accompanied by orotic acid accumulation, but this block does not fully account for the net reduction in uridine nucleotide synthesis. This suggests interference of the pyrimidine pathway at another locus, possibly by altered carbamyl phosphate synthetase activity. The mechanism for deoxyadenosine-mediated inhibition is obscure. Despite the demonstrable adenosine- and deoxyadenosine-mediated alterations of pyrimidine metabolism, these changes are not accompanied by marked interference of cell growth for both normal and ADA-deficient lymphoblasts. These data support the hypothesis that altered pyrimidine metabolism is not the basis for the immune disorder in patients with deficiency of ADA.