Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.

Abstract

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 and enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP detoxifies adenosine by converting it to inosine (10). The hypotheses then differ in their proposed mechanisms by which adenosine exerts its cytotoxic effects in cells incapable of eliminating this purine nucleoside. It has been proposed that cyclic AMP mediates the cytotoxic effects of adenosine (11,19), that the accumulated nucleotides of adenosine induce a pyrimidine nucleotide starvation (10, 12) or inhibit glycolysis (5), and that adenosine combines intracellularly with homocysteine to form S-adenosylhomocysteine, which in turn acts as a potent inhibitor of methylation reactions, including the methylation of newly synthesized DNA (20).There are specific objections to most of these proposals. In a model system, Ullman et al. (12) We have observed very abnormal levels of 2'-deoxyadenosine triphosphate (dATP) in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent, adenosine deaminase-deficient patient. Furthermore, we have followed the loss of erythrocyte dATP in two unrelated adenosine deaminasedeficient, immunodeficient patients after the infusion of erythrocytes containing the missing enzyme activity.f To whom reprint requests should be addressed

The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry

“…Finally, the benign condition called 'partial' ADA deficiency is characterized by a decreased enzyme activity in erythrocytes, but a residual enzyme activity in leukocytes and other nucleated cells [6]. In the early onset form, the severe functional defect of the enzyme ADA leads to the accumulation of toxic metabolites, represented primarily by 2-deoxyadenosine (dAdo) and dATP, the phosphorylated end product of the ADA substrate dAdo [7]; on turn increased dAdo levels inactivate the enzyme Sadenosylhomocysteine hydrolase and result in inhibition of transmethylation of nucleic acids, proteins, and lipids [8].…”

Transition-State Variation in Human, Bovine, and Plasmodium falciparum Adenosine Deaminases

“…The set of KIEs for the three ADAs were determined under competitive conditions. The intrinsic [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] N], [6-13 C], and [6- 30 Adenylate kinase (AK), pyruvate kinase (PK), hexokinase, and bovine spleen adenosine deaminase (BtADA) were purchased from Sigma. Phospho-D-ribosyl-1-pyrophosphate (PRPP) synthase and adenine phosphoribosyltransferase (APRTase) were purified according to the methods reported previously.…”

CD26 Expression Correlates with a Reduced Sensitivity to 2′-Deoxycoformycin-Induced Growth Inhibition and Apoptosis in T-Cell Leukemia/Lymphomas

“…Therefore, drugmediated inhibition of ADA leads to the accumulation of dAdo and its triphosphate form, dATP, in cell cytoplasms (6,7). These metabolites are able to determine a decrease of DNA synthesis with a subsequent impairment of cell proliferation (6,7). In the case of dATP, this happens through a direct block of the activity of ribonucleotide reductase, the enzyme catalyzing the synthesis of DNA precursor deoxynucleotides (8).…”

“…Therefore, drugmediated inhibition of ADA leads to the accumulation of dAdo and its triphosphate form, dATP, in cell cytoplasms (6,7). These metabolites are able to determine a decrease of DNA synthesis with a subsequent impairment of cell proliferation (6,7).…”