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

Activities of adenosine deaminase (ADA), adenosine kinase (AK), adenine phosphoribosyltransferase (APRT), hypoxanthine guanine phosphoribosyltransferase (HGPRT), and purine nucleoside phosphorylase (PNP), all enzymes of the purine interconversion system, were determined in lymphocytes of 25 patients with chronic lymphatic leukemia (CLL) and in 23 controls. A statistically significant decrease of PNP activities and a reduction of ADA activities at borderline levels were found in the patients, whereas for the other enzymes assayed no deviation from normal values was observed.
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PMID:Enzymes of the purine interconversion system in chronic lymphatic leukemia: decreased purine nucleoside phosphorylase and adenosine deaminase activity. 11 97

Phenotype distributions of some genetic polymorphisms are reported in a sample of 721 diabetics and 515 non-diabetic, non-blood donor controls. Reference is also made, in the case of the ABO and Rhesus systems, to previously published results for blood donors resident in the Durham area. Non-insulin-taking diabetics show an increased frequency of blood group A1 (and A1 + A2) when compared with controls. This difference is particularly marked in male diabetics. When diabetics are compared with age matched controls, the difference is confined to the older cases. It is proposed that this effect is predominantly the result of a deficiency of group A1 in controls rather than the result of increased susceptibility to the disease among A1 people. No association with any of the Rhesus phenotypes is shown. In non-diabetics, the results suggest an enhanced survival value for the rr genotype. No significant associations are seen when the MNSs, Kell, Lewis, Duffy, haptoglobin, red cell acid phosphatase, phosphoglucomutase, adenylate kinase, and adenosine deaminase distributions in these groups of subjects are compared.-
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PMID:Genetic polymorphisms in diabetics and non-diabetics. 11 8

The inhibition of adenovirus multiplication by adenine arabinoside was determined by yield reduction in one-step multiplication cycle. Inhibition was greatly enhanced by an adenosine deaminase inhibitor (2-deoxycoformycin) in concentrations down to 10 ng/ml. Adenovirus types from four subgroups showed similar results. However, the enhancing effect of adenosine deaminase inhibitor was great in HeLa cells, moderate in human fibroblasts, and negligible in Vero cells. This difference could be explained by different concentrations of adenosine deaminase found in cell homogenates.
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PMID:Adenine arabinoside inhibition of adenovirus replication enhanced by an adenosine deaminase inhibitor. 11 38

Conversion of adenosine to inosine is decreased in adenosine deaminase (ADA)-deficient fibroblasts at all concentrations of adenosine tested. Adenosine is not differentially toxic to ADA-deficient fibroblasts except at very high (5 X 10(-4) -1 X 10(-3) M) adenosine levels. Conversion of [14C] adenosine to GTP is not decreased in ADA-deficient cells compared with control cell strains. Adenosine conversion to ATP is the same as that in mutant cells except at high nonphysiologic concentrations, at which it is slightly decreased in ADA-deficient fibroblasts. This effect is probably not related to the biochemical pathology of ADA-deficient lymphocytes in vivo. Uridine, a pyrimidine compound, "rescues" control cells from the effects of adenosine toxicity, as previously reported, but it has no protective effect on ADA-deficient fibroblasts. This suggests that uridine will have no therapeutic role in the treatment of the ADA-deficient form of severe combined immunodeficiency (SCID) disease.
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PMID:Purine dysfunction in cells from patients with adenosine deaminase deficiency. 13 30

Activity of adenosine deaminase (ADA), an enzyme known to be deficient in some patients with severe combined immunodeficiency, increased three-fold within a 24-hour exposure of human peripheral blood lymphocytes to phytohaemagglutinin (PHA) in culture. This increase took place before the onset of DNA synthesis. Increased levels of ADA activity were also observed in lymphocytes incubated with pokeweed mitogen (PWM) for 60 hr. DNA synthesis induced by PHA, PWM or mixed lymphocyte cultures (MLC) was strongly inhibited by adenosine at concentrations of 10(-4) M or higher when human peripheral blood lymphocytes were cultured in a medium supplemented with horse serum, which lacks ADA. 10(-6)-10(-8) M coformycin, a potent inhibitor of ADA, inhibited PHA-, PWM- and MLC-induced DNA synthesis to a variable extent, whereas thymidine incorporation induced by Salmonella lipopolysaccharide (LPS) in mouse spleen cell cultures was strongly inhibited (by 75% or more) by 10(-6) M coformycin. Combination of 10(-7)-10(-8) M coformycin and 10(-4)-10(-5) M adenosine synergistically inhibited mitogen- or MLC-induced DNA synthesis in human and mouse lymphocyte cultures. These results, together with observations on children with ADA deficiency, provide evidence that adenosine deaminase is highly important for lymphocyte proliferation. Human peripheral blood lymphocytes incubated with PHA, 10(-5) M adenosine and 10(-7) M coformycin showed some cytotoxicity whereas the rate of 51Cr release from normal lymphocytes was not modified by the drugs. These findings suggest that in vivo clones of lymphocytes responding to specific antigens might be eliminated by coformycin, which may prove to be useful as a specific immunosuppressive agent.
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PMID:Role of adenosine deaminase in lymphocyte proliferation. 13 8

Suckling rats were exposed for 15 and 30 days to manganese through the milk of nursing dams receiving 15 mg MnCl2--4H2O/kg/day orally and after which the neurological manifestations of metal poisoning were studied. No significant differences in the growth rate, developmental landmarks and walking movements were observed between the control and manganese-exposed pups. The metal concentration was significantly increased in the brain of manganese-fed pups at 15 days and exhibited a further three-fold increase over the control, at 30 days. The accumulation of the metal in the brain of manganese-exposed nursing dams was comparatively much less. A significant decrease in succinic dehydrogenase, adenosine triphosphatase, adenosine triphosphatase, adenosine deaminase, acetylcholine esterase and an increase in monoamine oxidase activity was observed in the brain of experimental pups and dams. The results suggest that the developing brain may also be susceptible to manganese.
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PMID:Effect of manganese on neonatal rat: manganese concentration and enzymatic alterations in brain. 14 Nov 94

The effects of manganese and ethanol interaction on some chemical constituents of the liver and serum of rats were investigated in order to assess the influence of these substances in inducing susceptibility to manganese poisoning. Manganese and ethanol alone or in combination were administered to the rats as drinking solutions for a period of 30 days. Both the chemicals had a synergistic effect in altering the activity of SDH and ATPase in the liver of rats. The combined treatment also produced significant increase in the activity of adenosine deaminase and alpha-amylase in the liver and serum respectively. Furthermore, the accumulation of manganese in the liver and the increase in the calcium content of the serum were significantly greater after combined ethanol and manganese administration--than either of them alone. These alterations indicate that the toxic effects of manganese are enhanced when the metal and ethanol interact in the biological system.
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PMID:The interaction between manganese and ethanol in rats. 15 83

In fat cells isolated from the parametrial adipose tissue of rats, the addition of purified adenosine deaminase increased lipolysis and cyclic adenosine 3':5'-monophosphate (cyclic AMP) accumulation. Adenosine deaminase markedly potentiated cyclic AMP accumulation due to norepinephrine. The increase in cyclic AMP due to adenosine deaminase was as rapid as that of theophylline with near maximal effects seen after only a 20-sec incubation. The increases in cyclic AMP due to crystalline adenosine deaminase from intestinal mucosa were seen at concentrations as low as 0.05 mug per ml. Further purification of the crystalline enzyme preparation by Sephadex G-100 chromatography increased both adenosine deaminase activity and cyclic AMP accumulation by fat cells. The effects of adenosine deaminase on fat cell metabolism were reversed by the addition of low concentrations of N6-(phenylisopropyl)adenosine, an analog of adenosine which is not deaminated. The effects of adenosine deaminase on cyclic AMP accumulation were blocked by coformycin which is a potent inhibitor of the enzyme. These findings suggest that deamination of adenosine is responsible for the observed effects of adenosine deaminase preparations. Protein kinase activity of fat cell homogenates was unaffected by adenosine or N6-(phenylisopropyl)adenosine. Norepinephrine-activated adenylate cyclase activity of fat cell ghosts was not inhibited by N6-(phenylisopropyl)adenosine. Adenosine deaminase did not alter basal or norepinephrine-activated adenylate cyclase activity. Cyclic AMP phosphodiesterase activity of fat cell ghosts was also unaffected by adenosine deaminase. Basal and insulin-stimulated glucose oxidation were little affected by adenosine deaminase. However, the addition of adenosine deaminase to fat cells incubated with 1.5 muM norepinephrine abolished the antilipolytic action of insulin and markedly reduced the increase in glucose oxidation due to insulin. These effects were reversed by N6-(phenylisopropyl)adenosine. Phenylisopropyl adenosine did not affect insulin action during a 1-hour incubation. If fat cells were incubated for 2 hours with phenylisopropyl adenosine prior to the addition of insulin for 1 hour there was a marked potentiation of insulin action. The potentiation of insulin action by prior incubation with phenylisopropyl adenosine was not unique as prostaglandin E1, and nicotinic acid had similar effects.
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PMID:Effects of adenosine deaminase on cyclic adenosine monophosphate accumulation, lipolysis, and glucose metabolism of fat cells. 16 37

A unique seven-membered heterocyclic-ring inhibitor of adenosine deaminase was studied. One preparation of the compound inhibited replication of herpes simplex virus in the absence of adenine arabinoside. In this capacity, the minimal inhibitory concentration of deaminase inhibitor for herpes simplex virus type 1 (HSV-1), with 50 percent reduction of plaque-forming units as the end point, was 37.7 mug/ml. This activity compared favorably with the inhibitory activity of ara-hypoxanthine (34.1 mug/ml). Another preparation of deaminase inhibitor lacked antiviral activity. On the other hand, the adenosine deaminase inhibitor was active at a concentration of 0.009 mug/ml as a potentiator of the inhibition of HSV-1 by adenine arabinoside. The potentiation of adenine arabinoside by deaminase inhibitor is about 4,000 times more potent than the activity of the direct inhibitory effect on HSV-1. The nature of the possible contaminant of the preparation in question is unknown. Coformycin, another inhibitor of adenosine deaminase, had no antiviral activity in the absence of adenine arabinoside.
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PMID:Antiviral activity of an adenosine deaminase inhibitor: decreased replication of herpes simplex virus. 16 17


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