Mechanism of Adenosine Triphosphate Catabolism Induced by Deoxyadenosine and by Nucleoside Analogues in Adenosine Deaminase-inhibited Human Erythrocytes1

The mechanism of the depletion of ATP, recorded in the erythrocytes of adenosine deaminase-deficient children and of leukemia patients treated with deoxycoformycin, »asinvestigated in normal human eryth rocytes treated with this inhibitor of adenosine deaminase. Deoxyadeno sine, which accumulates in both clinical conditions, provoked a dosedependent accumulation of dATP, depletion of ATP, and increases in the production of inosine plus hypoxanthine. Concomitantly, there was an increase of AMP and IMP, but not of adenosine, indicating that catabolism proceeded by way of AMP deaminase. A series of nucleoside analogues (9-/3-D-arabinofuranosyladenine, A*-methyladenosine, 6-methylmercaptopurine ribonucleoside, tubercidin, ribavirin, and ¿V-I-ribosyl5-aminoimidazole-4-carboxamide riboside) also stimulated adenine nucleotide catabolism and increased AMP and IMP to various extents. The effects of deoxyadenosine and of the nucleoside analogues were prevented by 5'-iodotubercidin, an inhibitor of adenosine kinase. Strikingly, they were reversed if the inhibitor was added after the accumulation of nucleotide analogues and initiation of adenine nucleotide catabolism. Further analyses revealed linear relationships between the rate of phosphorylation of deoxyadenosine and nucleoside analogues and the increase in AMP and between the elevation of the latter above a threshold concentration of 10 UM and the rate of adenine nucleotide catabolism. Kinetic studies with purified erythrocytic AMP deaminase, at physiolog ical concentrations of its effectors, showed that the enzyme is nearly inactive up to 10 UMAMP and increases in activity above this threshold. We conclude that the main mechanism whereby deoxyadenosine and nucleoside analogues stimulate catabolism of adenine nucleotides by way of AMP deaminase in erythrocytes is elevation of AMP, secondary to the phosphorylation of the nucleosides.