Mechanism of deoxyadenosine-induced catabolism of adenine ribonucleotides in adenosine deaminase-inhibited human T lymphoblastoid cells

Publisher Website
Google Scholar
Abstract
Loss of ATP accompanying accumulation of dATP occurs in the erythrocytes and lymphoblasts of patients with T lymphocytic leukemia during treatment with deoxycoformycin, an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) that causes the accumulation of deoxyadenosine. The mechanisms responsible for adenine ribonucleotide depletion in cultured human CEM T lymphoblastoid cells treated with deoxycoformycin and deoxyadenosine was studied. Accumulation of dATP was accompanied by depletion of total soluble adenine ribonucleotides without change in the adenylate energy charge, by the route ATP .fwdarw. AMP .fwdarw. IMP .fwdarw. inosine .fwdarw. hypoxanthine; conversion of IMP to AMP and de novo purine synthesis were inhibited in these cells. ATP degradation did not occur in a mutant of CEM that was incapable of phosphorylating deoxyadenosine, or in a B cell line with very limited ability to accumulate dATP. dATP and ATP were both able to markedly stimulate the deamination of AMP by lymphoblast AMP deaminase; dAMP was a poor substrate for this enzyme (Km = 2.4 mM, vs. 0.4 mM for AMP). Similarly, dATP and ATP caused marked activation of IMP dephosphorylation by a lymphoblast cytoplasmic nucleotidase. Inhibition of intracellular AMP deaminase with coformycin prevented degradation of adenine ribonucleotides without affecting dATP accumulation. ATP-dependent phosphorylation of deoxyadenosine may generate ADP and AMP. Simultaneously, dATP accumulation stimulates deamination of AMP, but not dAMP, and the dephosphorylation of IMP to inosine. Coupling of AMP degradation to ATP utilization in deoxyadenosine phosphorylation maintains the adenylate energy charge despite net depletion of cellular ATP.