Biochemical basis for lymphocyte dysfunction in adenosine deaminase and purine nucleoside phosphorylase deficiencies.

Abstract

Deoxypurine metabolism in human thymocytes and mature T lymphocytes differs remarkably from other cell types (1–3). When the normal pathways of deoxyadenosine and deoxyguanosine degradation are lacking in adenosine deaminase (ADA) and purine nucleoside Phosphorylase (PNP) deficient patients, human T cells exposed to even micromolar concentrations of the respective nucleosides progressively accumulate dATP or dGTP intracellularly. The dATP and dGTP increase to toxic levels primarily in this cell type because(i) in T cells deoxynucleoside phosphorylating activity substantially exceeds deoxynucleotide dephosphorylating activity, and (ii) nucleotides, as opposed to nucleosides, do not readily traverse cell membranes, and hence are trapped intracellularly.