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)

Coformycin, which is an inhibitor of adenosine deaminase, significantly inhibited in vitro blastogenic responses of human lymphocytes to both phytohaemagglutinin (PHA) and pokeweed mitogen (PWM), whereas blastogenic responses to bacterial lipopolysaccharide (LPS) were rather enhanced by the addition of coformycin. Blastogenic responses of lymphocytes to PHA and PWM were markedly suppressed by the addition of adenosine, which is a substrate of adenosine deaminase. Allopurinol, which is an inhibitor of xanthine oxidase, inhibited blastogenic responses of human lymphocytes to PHA, PWM, and bacterial LPS. Inosine (a substrate of purine nucleoside phosphorylase) and hypoxanthine (a substrate of xanthine oxidase) showed no or only a small effect on blastogenic responses of human lymphocytes. These results suggest that adenosine deaminase activity is associated with the T-cell response but not with the B-cell response and that the impaired T-cell response in adenosine deaminase deficiency is the result of intracellular retention of adenosine in T cells. The results also suggest that purine nucleoside phosphorylase or xanthine oxidase activity is associated with both T- and B-cell responses.
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PMID:Purine metabolic enzymes in lymphocytes. IV. Effects of enzyme inhibitors and enzyme substrates on the blastogenic responses of human lymphocytes. 392 75

Complete genetic deficiency of adenosine deaminase (ADA) results in a fatal syndrome of severe combined immunodeficiency (SCID). Genetic partial deficiency of ADA, with no detectable enzyme activity in erythrocytes but with variable amounts of enzyme activity detectable in other cells, is usually associated with normal immunologic function but can give rise to a late-onset, cellular immunodeficiency syndrome. We have previously described four different mutant alleles in four such partially ADA-deficient children. We have now examined ADA in lymphoid cells from five additional newly ascertained children with partial ADA deficiency with respect to electrophoretic mobility in starch gel, isoelectric point, heat-stability, and apparent Km and Vmax. These techniques identify at least five different abnormal alleles in these five additional unrelated subjects. Three of these abnormal alleles result in expression of abnormal allelic isozymes (allozymes) different from those previously described. These are: (1) an acidic allozyme that is less acidic than the acidic allozyme we have previously reported; (2) an allozyme that is even less acidic than (1); and (3) an allozyme with apparently normal charge but which is so heat sensitive that the lability to heat can easily be detected at physiologic to febrile temperatures. Two abnormal alleles detected in these five children could correspond with previously reported mutants. These are (4) a basic allozyme that could (but probably doesn't) correspond to the basic allozyme we have previously reported and (5) a "null" allele that cannot be differentiated by these methods from any other "null" allele seen in complete ADA- -SCIDs. Three of the five new patients are genetic compounds, identified either by the presence of two electrophoretically distinguishable allozymes or by family studies that demonstrate presence of a "null" allele in addition to an electrophoretically abnormal allozyme. In three patients, one or both allozymes are phenotypically indistinguishable from an abnormal allozyme also seen in a different individual. Determination of the nucleotide sequence will be required to determine whether or not the phenotypically indistinguishable mutations are indeed genotypically identical. The newly ascertained individuals appear to share a common ethnic West Indian background, out of proportion to the frequency of this ethnic background in the newborn population from which they were ascertained, suggesting that partial ADA deficiency may confer a selective advantage to the homozygous or heterozygous phenotype.
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PMID:Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency. 394 19

The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
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PMID:Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency. 395 May 45

Hereditary deficiency of adenosine deaminase (ADA) usually causes profound lymphopenia with severe combined immunodeficiency disease. Cells from patients with ADA deficiency contain less than normal, and sometimes undetectable, amounts of ADA catalytic activity and ADA protein. The molecular defects responsible for hereditary ADA deficiency are poorly understood. ADA messenger RNAs and their translation products have been characterized in seven human lymphoblast cell lines derived as follows: GM-130, GM-131, and GM-2184 from normal adults; GM-3043 from a partially ADA deficient, immunocompetent !Kung tribesman; GM-2606 from an ADA deficient, immunodeficient child; CCRF-CEM and HPB-ALL from leukemic children. ADA messenger (m)RNA was present in all lines and was polyadenylated. The ADA synthesized by in vitro translation of mRNA from each line reacted with antisera to normal human ADA and was of normal molecular size. There was no evidence that posttranslational processing of ADA occurred in normal, leukemic, or mutant lymphoblast lines. Relative levels of specific translatable mRNA paralleled levels of ADA protein in extracts of the three normal and two leukemic lines. However, unexpectedly high levels of ADA specific, translatable mRNA were found in the mutant GM-2606 and GM-3043 lines, amounting to three to four times those of the three normal lines. Differences in the amounts of ADA mRNA and rates of ADA synthesis appear to be of primary importance in maintaining the differences in ADA levels among lymphoblast lines with structurally normal ADA. ADA deficiency in at least two mutant cell lines is not caused by deficient levels of translatable mRNA, and unless there is some translational control of this mRNA, the characteristic cellular ADA deficiency is most likely secondary to synthesis and rapid degradation of a defective ADA protein.
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PMID:Adenosine deaminase messenger RNAs in lymphoblast cell lines derived from leukemic patients and patients with hereditary adenosine deaminase deficiency. 613 54

Cloned cDNA sequences of human adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4) have been isolated from a cDNA library constructed in bacteriophage lambda gt10. The cDNA for the library was prepared from poly(A)+ RNA isolated from a human T-lymphoblast cell line, CCRF-CEM. The library was initially screened by differential plaque hybridization to labeled cDNA prepared from human T- and B-lymphoblast cell lines with a 21-fold difference in levels of translatable ADA mRNA. Two recombinants containing cloned cDNA sequences for ADA were identified by hybridization-selected translation. Both recombinants contained approximately 1,600 base pairs of inserted human DNA. Restriction maps of the two inserts were not identical. One contained approximately 40 base pairs of additional DNA toward the center of the cDNA. The cloned cDNA specifically hybridized to five fragments generated by HindIII digestion of human genomic DNA. It also hybridized to human lymphoblast RNA species 1.6 and 5.8 kilobases in length. The cDNA was used as a probe to estimate ADA mRNA levels in human lymphoblast cell lines. ADA mRNA levels correlate closely with levels of ADA catalytic activity and ADA protein in cell lines containing structurally normal ADA. A leukemic T-lymphoblast line produced 6 to 9 times as much ADA protein and ADA mRNA as transformed B-lymphoblast lines. Two mutant B-lymphoblast lines from patients with hereditary ADA deficiency contained unstable ADA protein but had 3 to 4 times the normal level of ADA mRNA.
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PMID:Cloning of cDNA sequences of human adenosine deaminase. 620 Aug 75

Deoxyadenosine (AdR) appears to be central to the molecular events mediating immunodeficiency in children born with adenosine deaminase (ADA) deficiency but it is still uncertain whether lymphotoxicity is due to AdR directly inhibiting transmethylation reactions in which S-adenosylmethionine is the methyl group donor, or is due to phosphorylation of AdR to deoxyadenosine triphosphate (dATP) which then inhibits ribonucleotide reductase or is due to other mechanisms. Using AdR and the ADA inhibitor deoxycoformycin (dCF) and assessing cell viability, nucleoside incorporation into RNA and DNA, as well as measuring deoxyribonucleoside triphosphate (dNTP) concentrations and S-adenosylhomocysteine (SAH) hydrolase activity, we have studied various types of human lymphoid cells and demonstrated in them the relative importance of the above two mechanisms of AdR toxicity. Treatment of normal resting peripheral blood lymphocytes in culture with AdR and dCF resulted in impaired viability. Although elevated dATP levels as well as decreased SAH hydrolase activities were both observed, the failure of a known inhibitor of ribonucleotide reductase (hydroxyurea) to produce toxicity, and the inability of deoxycytidine (CdR) to achieve a rescue effect, point to another mechanism, possibly inhibition of trans-methylation or ATP depletion being the more likely causes of toxicity in resting lymphocytes. The same mechanism may well account for the rapid and severe lymphopenia in patients treated with dCF. On the other hand, in cultured lymphoblasts in the exponential phase of growth. AdR and dCF produced marked inhibition of growth and cell death both in a Thy-ALL line and in a c-ALL line, in the absence of significant inhibition of SAH hydrolase, but with a substantial elevation in dATP concentrations and depressed levels of the other dNTP. Minor toxicity occurred in a proliferating B lymphoblast line despite almost complete inactivation of SAH hydrolase. These observations indicate inhibition of ribonucleotide reductase as the more likely mechanism of toxicity in rapidly proliferating lymphocytes. Other T-cells actively synthesizing DNA, such as PHA-stimulated or MLC activated lymphocytes and T-lymphoid colony forming cells, are also likely to be affected by the same mechanism. Indeed in PHA-stimulated lymphocytes, deoxycytidine caused significant although incomplete rescue from toxicity due to dCF and AdR. In patients with ADA deficiency or treated with ADA inhibitors, both mechanisms could be operative. These observations are also relevant to the possible use of dCF and AdR as immunosuppressive agents and for the removal of T-cells or residual Thy-ALL blasts from bone marr
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PMID:Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: relevance to the therapeutic use of inhibitors of adenosine deaminase. 623 Oct 47

A child diagnosed at birth as deficient in red blood cell adenosine deaminase (ADA) but with substantial residual lymphocyte ADA has been evaluated for two and one-half years. The only immunologic abnormality observed was hypogammaglobulinemia during the fifth month of life. This was unexpected because children with total ADA deficiency either have severe combined immunodeficiency or selectively greater impairment of cellular than humoral immunity. The absence of severe combined immunodeficiency in this child was associated with normal lymphocyte content of ATP, dATP, and cyclic 3'5'-adenosine monophosphate, potentially toxic metabolites which are elevated in ADA-deficient immunodeficient children.
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PMID:Adenosine deaminase deficiency without immunodeficiency: clinical and metabolic studies. 625 20

During phagocytosis and membrane perturbation, mouse macrophages generate superoxide in direct proportion to their intracellular adenosine deaminase activity. It is proposed that since adenosine deaminase controls the amount of substrate available to xanthine oxidase, and the latter produces superoxide during turnover of its substrates, the purine salvage pathway is an important contributor to the superoxide requirement of macrophages. It is further proposed that this may be the basis for the mechanism of the association of adenosine deaminase deficiency with immunodeficiency.
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PMID:Adenosine deaminase activity and superoxide formation during phagocytosis and membrane perturbation of macrophages. 626 29

Phagocytosis and membrane perturbation in mouse macrophages results in an increased superoxide ion production which is in direct proportion to the concomitant increase in adenosine deaminase activity. Since adenosine deaminase activity controls the amount of substrate available to xanthine oxidase, and the latter produces superoxide during turnover of its substrates, it is proposed that the purine salvage pathway is an important source of the superoxide requirement of macrophages. It is further proposed that this may be the basis, at least in part, for the mechanism of the association of immunodeficiency with adenosine deaminase deficiency.
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PMID:Positive correlation between adenosine deaminase activity and superoxide formation during phagocytosis. 630 Feb 72

Adenosine deaminase (EC 3.5.4.4. - ADA) deaminates adenosine and deoxyadenosine to inosine and deoxyinosine. The distribution of ADA isoenzymes depends on a binding protein. Purine nucleoside phosphorylase (EC 2.4.2.1. - PNP) catabolizes inosine and guanosine to hypoxanthine and guanine. Patients with severe combined immuno-insufficiency often suffer from a congenital ADA deficiency. The PNP deficiency is associated with severely defective T-cell immunity and normal B-cell immunity. Deficiency of ADA leads to an accumulation of adenosine, deoxyadenosine, adenine nucleotides (cAMP, dATP). In PNP deficiency an increased production of inosine, guanosine, deoxyinosine and deoxyguanosine was found. The pathogenesis of the immuno-insufficiency is to be traced back to disturbances in the purine metabolism interfering with the mitogenically induced lymphocyte transformation and other lymphocyte functions, as determined by in vitro tests. Deoxyadenine inhibits the ribonucleoside diphosphate reductase and synthesis of DNA. The overproduction of S-adenosyl-L-homocysteine inhibits methyltransferase reactions and 2'-deoxyadenosine the S-adenosylhomocysteine hydrolase. A decrease of ADA activities was found in T-lymphocytes of patients with Hodgkin's disease. Measurements of ADA activity in patients with leukemias do not explain the impairment of the cellular immune response in leukemias and may be regarded as indicator of increased purine metabolism. The ADA activities are increased in patients with acute immature and chronic myeloic leukemias depending on the activity of the disease. The ADA activity is low in chronic lymphatic leukemia. ADA inhibitors were used for the treatment of T-cell leukemias.
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PMID:[Immune insufficiency in enzyme defects of purine metabolism]. 630 5


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