Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s)

Publisher Website
Google Scholar
Abstract
Inherited deficiencies of the enzymes adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) and purine nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase; EC 2.4.2.1) preferentially interfere with lymphocyte development while sparing most other organ systems. Previous experiments showed that through the action of specific kinases, nucleosides can be trapped intracellularly in the form of 5''-phosphates. The ability of newborn human tissues to phosphorylate adenosine and deoxyadenosine, the substrate of adenosine deaminase, and also inosine, deoxyinosine, guanosine and deoxyguanosine, the substrates of purine nucleoside phosphorylase was measured. Substantial activities of adenosine kinase were found in all tissues studied; guanosine and inosine kinases were detected in none. The ability to phosphorylate deoxyadenosine, deoxyinosine and deoxyguanosine was largely confined to lymphocytes. Adenosine deaminase, but not purine nucleoside phosphorylase, showed a similar lymphoid predominance. Deoxyadenosine, deoxyinosine and deoxyguanosine were toxic to human lymphoid cells. The toxicity of deoxyadenosine was reversed by the addition of deoxycytidine, but not uridine, to the culture medium. In adenosine deaminase and purine nucleoside phosphorylase deficiency, toxic deoxyribonucleosides produced by many tissues are probably selectively trapped in lymphocytes by phosphorylating enzyme(s).