Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation.

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Abstract
Accumulation of dATP derived from 2''-deoxyadenosine (dAdo), causing inhibition of ribonucleotide reductase and depletion of the other deoxynucleotide substrates required for DNA synthesis, has been suggested as the cause of the lymphopenia and immune defect in inheritable deficiency of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4). dAdo inactivates the enzyme S-adenosylhomocysteine hydrolase (AdoHcyase; S-adenosyl-L-homocysteine hydrolase, EC 3.3.1.1) which is involved in the catabolism of S-adenosyl-L-homocysteine (AdoHcy), a product and a potent inhibitor of S-adenosylmethionine-dependent transmethylation. Whether inactivation of AdoHycase might also contribute to dAdo toxicity to adenosine deaminase-inhibited cells was studied. dAdo rapidly inactivates intracellular AdoHcyase and causes the accumulation of AdoHcyin WI-L2 human B lymphoblastoid cells. Low concentrations of adenosine (Ado), which block binding of dAdo to purified AdoHcyase, prevented inactivation of intracellular AdoHcyase and lessened the growth-inhibitory effect of dAdo. A mutant of this cell line which lacks Ado kinase and accumulates endogenously synthesized Ado was resistant to the effects of dAdo on growth and AdoHcyase activity. The mutant accumulated far less dATP from dAdo than did its parent and was resistant to the inhibitory effect of dAdo on DNA synthesis, indicating that Ado kinase is involved in dAdo phosphorylation in these cells. Combinations of deoxycytidine, thymidine and deoxyguanosine that could prevent dATP-mediated depletion of deoxynucleotide pools but not AdoHcyase inactivation were less effective than Ado in preventing dAdo toxicity to normal lymphoblasts. Inactivation of AdoHycase and dATP accumulation contributes to dAdo toxicity.

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