Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxyadenosine and deoxyguanosine are toxic to human lymphoid cells in culture and have been implicated in the pathogenesis of the immunodeficiency states associated with adenosine deaminase and purine nucleoside phosphorylase deficiency, respectively. We have studied the relative incorporation of several labeled nucleosides into DNA and into nucleotide pools to further elucidate the mechanism of deoxyribonucleoside toxicity. In the presence of an inhibitor of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA], 5 muM], deoxyadenosine (1-50 muM) progressively decreased the incorporation of thymidine, uridine, and deoxyuridine into DNA, but did not affect uridine incorporation into RNA. This decrease in DNA synthesis was associated with increasing dATP and decreasing dCTP pools. Likewise, incubation of cells with deoxyguanosine caused an elevation of dGTP, depletion of dCTP, and inhibition of DNA synthesis. To test the hypothesis that dATP and dGTP accumulation inhibit DNA synthesis by inhibiting the enzyme ribonucleotide reductase, simultaneous rates of incorporation of [(3)H]uridine and [(14)C]thymidine into DNA were measured in the presence of deoxyadenosine plus EHNA or deoxyguanosine, and in the presence of hydroxyurea, a known inhibitor of ribonucleotide reductase. Hydroxyurea (100 muM) and deoxyguanosine (10 muM) decreased the incorporation of [(3)H]uridine but not of [(14)C]thymidine into DNA; both compounds also substantially increased [(3)H]cytidine incorporation into the ribonucleotide pool while reducing incorporation into the deoxyribonucleotide pool. In contrast, deoxyadenosine plus EHNA did not show this differential inhibition of [(3)H]uridine incorporation into DNA, and the alteration in [(3)H]cytidine incorporation into nucleotide pools was less impressive. These data show an association between accumulation of dATP or dGTP and a primary inhibition of DNA synthesis, and they provide support for ribonucleotide reductase inhibition as the mechanism responsible for deoxyguanosine toxicity. Deoxyadenosine toxicity, however, appears to result from another, or perhaps a combination of, molecular event(s).
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PMID:Purinogenic immunodeficiency diseases. Differential effects of deoxyadenosine and deoxyguanosine on DNA synthesis in human T lymphoblasts. 11 1

Deoxyadenosine, which was phosphorylated to dATP, inhibited DNA synthesis in malignant cells. However, on incubation of the substance in vitro with Zaidela ascites hepatoma cells the inhibitory effect was gradually decreased due to dephosphorylation of dATP and to deamination of deoxyadenosine to deoxyinosine. In order to prolong the inhibition of nucleic acids synthesis, N-6-methyl adenosine, which was recognized as an inhibitor of adenosine deaminase, was added to the cells. Optimal inhibition of DNA synthesis was observed in presence of deoxyadenosine and N-6-methyl adenosine at 1 with 10-minus 3 M concentration. Addition of N-6-methyl adenosine, after incubation with deoxyadenosine within 2 hrs, caused more prolonged inhibition of DNA and RNA synthesis than it was observed in presence of deoxyadenosine.
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PMID:[Action of deoxyadenosine on nucleic acid synthesis by tumor cells in the presence of a deaminase inhibitor]. 16 14

Addition of adenosine deaminase (ADA) restored in vitro responses of lymphocytes from a patient with ADA deficiency and severe combined immunodeficiency (SCID). Enzyme replacement therapy, using red blood cells as a source of encapsulated human ADA, restored both T and B cell function in this patient. Ten other ADA--SCID patients have been treated with this form of enzyme replacement and five have responded to therapy. Lymphocytes from ADA--SCID patients treated with enzyme replacement become immunocompetent but remain enzyme deficient. Studies of these cells provide evidence supporting both cyclic AMP- and dATP-mediated immunosuppressive mechanisms in ADA--SCID. These observations suggest that inhibition of cyclic AMP synthesis and/or deoxycytidine (and possibly thymidine) supplementation may be useful new biochemical approaches to the therapy of ADA--SCID.
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PMID:Enzyme replacement and other biochemical approaches to the therapy of adenosine deaminase deficiency. 22 49

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.
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PMID:Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. 27 65

The deoxynucleotide, dATP, is elevated 50- to 1,000-fold above normal in erythrocytes, lymphocytes, and bone marrow from a child with adenosine deaminase deficiency and severe combined immunodeficiency disease. The child, when 17 mo of age, was also excreting approximately 30 mg of deoxyadenosine per day in urine (normal is less than 0.1 mg/day). Urinary excretion of uric acid was decreased. Elevated dATP levels in lymphocytes and bone marrow, and increased urinary excretion of deoxyadenosine, persisted despite hypertransfusion of the child with irradiated erythrocytes from a donor with normal adenosine deaminase. Overproduction of deoxynucleotides by increased salvage of adenosine appears to be the primary metabolic abnormality in patients with adenosine de aminase deficiency.
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PMID:Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease. 30 54

Deoxyadenosine at low concentrations and in the presence of an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) is markedly toxic to lymphoblast cell lines of T cell origin but does not impair growth of B cell lines. Deoxyguanosine is also more toxic for T lymphoblasts. In the presence of deoxyadenosine or deoxyguanosine, elevation of the corresponding deoxyribonucleoside triphosphate (dATP or dGTP) occurs in T cell, but not in B cell, lines. The addition of deoxycytidine or dipyridamole results in lower dATP and dGTP levels and prevents deoxyribonucleoside toxicity. These findings provide a molecular basis for the immunodeficiency observed in individuals with several inborn errors of purine metabolism.
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PMID:Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells. 31 Oct 4

The rate of DNA synthesis in cultured diploid fibroblasts, nonmalignant human cells, is decreased by 50 microM 2'-deoxyadenosine when adenosine deaminase is inhibited and 2'-deoxyadenosine is phosphorylated to dATP. No inhibiton of DNA synthesis occurs with 100 microM adenosine under identical conditions or with 50 microM deoxyadenosine when adenosine deaminase is not blocked. Inhibition of DNA synthesis may be an important link between adenosine deaminase deficiency and severe combined immunodeficiency if the tissue culture model is relevant to lymphocyte function in man.
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PMID:Deoxyadenosine inhibits DNA synthesis in cultured human fibroblasts. 31 67

Accumulation of adenine deoxynucleotides (dATP and dADP) in the erythrocytes of a patient with adenosine deaminase (ADA) deficiency was confirmed. The patient, now 18 mo old, was treated with a bone marrow transplantation from his HLA identical sister at 7 mo of age. Before and after the transplant, his erythrocyte and lymphocyte ADA activities, as well as his erythrocyte nucleotide profiles, were measured. 10 wk after the marrow transplant, no ADA activity could be detected in his erythrocytes, whereas there was a mixture of donor and patient lymphocytes as measured by ADA assays and karyotyping. At the same time, both dATP and dADP had disappeared from his erythrocytes, which were entirely of patient origin. These findings indicate that partial engraftment of donor lymphocytes into an ADA-deficient patient is capable of "correcting" alterations of deoxynucleotide concentrations in the patient's ADA-deficient erythrocytes.
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PMID:Adenosine deaminase deficiency: disappearance of adenine deoxynucleotides from a patient's erythrocytes after successful marrow transplantation. 37 36

Deoxyadenosine was identified in the urine of a second child with almost undetectable levels of adenosine deaminase (ADA) in erythrocyte lysates. Deoxyadenosine excretion thus appears to be characteristic of ADA deficiency: the acid lability of deoxyadenosine (responsible for the frequent confusion of this abnormal urinary metabolite with adenine) may be used in screening for this defect by isotachophoresis. The deoxynucleotides dATP, dADP and dAMP found initially in the child's erythrocytes (in comparable amounts to ATP, ADP and AMP) disappeared after a successful marrow graft from an unrelated donor, as did the urinary deoxy metabolites. Erythrocyte ADA activity decreased after the marrow graft but was still greater than 10% of normal congruent to 10 weeks after the last red cell transfusion.
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PMID:Purine metabolism in adenosine deaminase deficiency. 38 57

Inherited deficiency of the purine salvage enzyme adenosine deaminase (ADA) gives rise to a syndrome of severe combined immunodeficiency (SCID). We have studied a 2.5-yr-old immunologically normal child who had been found to lack ADA in his erythrocytes during New York State screening of normal newborns. His erythrocytes were not detectably less deficient in ADA than erythrocytes of ADA(-)-SCID patients. In contrast, his lymphocytes and cultured long-term lymphoid cells contained appreciably greater ADA activity than those from patients with ADA(-)-SCID. This residual ADA activity had a normal molecular weight and K(m) but was markedly unstable at 56 degrees C. His residual erythrocytes-ADA activity also appeared to have diminished stability in vivo. ADA activity in lymphoid line cells of a previously reported erythrocyte-ADA-deficient!Kung tribesman was found to contain 50% of normal activity and to exhibit diminished stability at 56 degrees C. ATP content of erythrocytes from both partially ADA-deficient individuals was detectably greater than normal (12.3 and 6.1 vs. normal of 2.6 nmol/ml packed erythrocytes). However, the dATP content was insignificant compared to that found in erythrocytes of ADA(-)-SCID patients (400-1,000 nmol/ml packed erythrocytes). The New York patient, in contrast to normals, excreted detectable amounts of deoxyadenosine, but this was <2% of deoxyadenosine excreted by ADA(-)-SCID patients. Thus, the residual enzyme in cells other than erythrocytes appears to be sufficient to almost totally prevent accumulation of toxic metabolites.
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PMID:Erythrocyte adenosine deaminase deficiency without immunodeficiency. Evidence for an unstable mutant enzyme. 47 73


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