Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.
The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient ane enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP diminished. Using high-pressure liquid chromatography that resolves ATP and 2'-dATP, we have observed greater than 50-fold elevations of dATP in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent adenosine deaminase-deficient patient. The erythrocyte dATP in two unrelated adenosine deaminase-deficient, immunodeficient patients disappeared after infusion of normal erythrocytes. We propose that deoxyadenosine, a substrate of adenosine deaminase, is the potentially toxic substrate in adenosine deaminase deficiency, and that the mediator of the toxic effect is dATP, a recognized potent inhibitor of ribonucleotide reductase.
D000225:Adenine / Q000097:blood; D000241:Adenosine / Q000097:blood; D000243:Adenosine Deaminase / Q000172:deficiency*; D003838:Deoxyadenine Nucleotides / Q000097:blood*; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood*; D009000:Monocytes / Q000201:enzymology; D009700:Nucleoside Deaminases / Q000172:deficiency*
D003838:Deoxyadenine Nucleotides; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine
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