Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency.
Purine nucleoside phosphorylase (PNP) deficiency is associated with a severe defect in thymus-derived (T)-lymphocyte function combined with normal bone marrow-derived (B)-lymphocyte function. To investigate the role of this enzyme deficiency in the resulting immune dysfunction, we measured the levels of ribonucleoside and deoxyribonucleoside triphosphates in erythrocytes from two unrelated PNP-deficient, T-lymphocyte-deficient patients. Both PNP-deficient patients have abnormally high levels of deoxyguanosine triphosphate (deoxy-GTP) in their erythrocytes (5 and 8 nmol/ml packed erythrocytes). In contrast, normal controls and adenosine deaminase-deficient, immunodeficient patients do not have detectable amounts of deoxyGTP (<0.5 nmol/ml packed erythrocytes). We propose that deoxyguanosine, a substrate of PNP, is the potentially lymphotoxic metabolite in PNP deficiency. The mechanism of toxicity involves phosphorylation of deoxyguanosine to deoxyGTP, which acts as a potent inhibitor of mammalian ribonucleotide reductase.
D000243:Adenosine Deaminase / Q000172:deficiency; D000293:Adolescent; D002675:Child, Preschool; D003848:Deoxyguanine Nucleotides / Q000097:blood*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood* / Q000201:enzymology; D010430:Pentosyltransferases / Q000172:deficiency*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*
D003848:Deoxyguanine Nucleotides; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D000243:Adenosine Deaminase