title: 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 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.
mesh_terms: 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*
chemical_list: D003838:Deoxyadenine Nucleotides; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine
references.citation: Biochim Biophys Acta. 1962 Dec 31;61:885-96
references.pmid: 14033467
references.citation: Arch Biochem Biophys. 1962 Nov;99:304-12
references.pmid: 13967235
references.citation: Biochem Biophys Res Commun. 1960 Oct;3:392-6
references.pmid: 13726779
references.citation: Proc Natl Acad Sci U S A. 1977 Dec;74(12):5677-81
references.pmid: 202960
references.citation: J Pediatr. 1977 Jul;91(1):48-51
references.pmid: 195028
references.citation: Biochem Pharmacol. 1976 Dec 15;25(24):2713-9
references.pmid: 188424
references.citation: Cell. 1976 Oct;9(2):205-11
references.pmid: 184961
references.citation: Adv Exp Med Biol. 1977;76A:326-40
references.pmid: 857617
references.citation: N Engl J Med. 1976 Dec 23;295(26):1449-54
references.pmid: 825775
references.citation: Arch Biochem Biophys. 1976 Nov;177(1):10-5
references.pmid: 999281
references.citation: N Engl J Med. 1976 Dec 9;295(24):1337-43
references.pmid: 980079
references.citation: J Pediatr. 1976 Nov;89(5):732-6
references.pmid: 978319
references.citation: Lancet. 1972 Nov 18;2(7786):1067-9
references.pmid: 4117384
references.citation: Biochim Biophys Acta. 1969 Oct 7;192(1):141-4
references.pmid: 4310531
references.citation: J Biol Chem. 1972 Sep 10;247(17):5477-85
references.pmid: 4115637
references.citation: Lancet. 1972 Dec 16;2(7790):1316
references.pmid: 4117846
references.citation: Mol Pharmacol. 1972 Jul;8(4):410-6
references.pmid: 4403350
references.citation: Biochemistry. 1974 Aug 13;13(17):3601-6
references.pmid: 4367430
references.citation: Cell. 1974 Dec;3(4):367-74
references.pmid: 4374315
references.citation: Proc Natl Acad Sci U S A. 1973 Nov;70(11):3099-102
references.pmid: 4361676
references.citation: Mol Pharmacol. 1969 Jul;5(4):358-75
references.pmid: 4308509
references.citation: Proc Soc Exp Biol Med. 1970 Apr;133(4):1361-5
references.pmid: 4314861
references.citation: J Biol Chem. 1970 Oct 25;245(20):5360-8
references.pmid: 4319240
references.citation: Lancet. 1975 Oct 18;2(7938):743-6
references.pmid: 52774
references.citation: Lancet. 1975 Nov 1;2(7940):850-3
references.pmid: 53333
references.citation: Lancet. 1975 May 3;1(7914):1010-3
references.pmid: 48676
references.citation: FEBS Lett. 1976 Jul 1;66(1):102-6
references.pmid: 179893
references.citation: Science. 1975 Mar 14;187(4180):957-9
references.pmid: 167434
references.citation: J Clin Invest. 1976 Feb;57(2):274-82
references.pmid: 176177
references.citation: Cell Immunol. 1974 Jun;12(3):387-95
references.pmid: 4458966
references.citation: Pediatr Res. 1976 Jul;10(7):642-6
references.pmid: 132630
references.citation: J Pediatr. 1974 Feb;84(2):173-7
references.pmid: 4810724
references.citation: Science. 1973 Nov 23;182(4114):836-7
references.pmid: 4795749
references.citation: Biochim Biophys Acta. 1969 Feb 18;174(2):585-90
references.pmid: 4975704
references.citation: N Engl J Med. 1975 Apr 3;292(14):714-9
references.pmid: 1089883
references.citation: Proc Natl Acad Sci U S A. 1976 Aug;73(8):2867-71
references.pmid: 1066699
references.citation: J Clin Invest. 1976 Apr;57(4):1025-35
references.pmid: 947948
references.citation: J Biol Chem. 1976 Jul 10;251(13):4055-61
references.pmid: 932021
references.citation: Biochem Pharmacol. 1975 Aug 15;24(16):1495-8
references.pmid: 1238090
references.citation: Pediatr Res. 1976 Jan;10(1):67-70
references.pmid: 1246464
references.citation: Biochem Pharmacol. 1975 Jan 1;24(1):154-6
references.pmid: 1168469
references.citation: Biochem Pharmacol. 1975 Mar 15;24(6):693-701
references.pmid: 1125070
references.citation: J Biol Chem. 1966 Oct 25;241(20):4802-9
references.pmid: 5926184