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)

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

The biochemical mechanisms by which a genetically determined deficiency of adenosine deaminase leads to immunodeficiency are still poorly understood and prompted this study. We have examined the effects of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA) upon the response of human peripheral blood mononuclear cells to the mitogen concanavalin A (Con A). Cells isolated from normal volunteers were incubated in microtiter plates in the presence of various inhibitors, and the incorporation of tritrated thymidine or leucine into macromolecular material was measured after 64 h. EHNA at a concentration of 0.3 muM, which inhibited 90% of the adenosine deaminase (ADA) activity in a mononuclear preparation, impaired the incorporation of tritrated leucine into protein; 100 muM EHNA was the minimal concentration that inhibited thymidine uptake. The addition of 15 muM adenosine or 10 muM cyclic AMP to Con A-stimulated lymphocytes inhibited leucine uptake, while millimolar concentrations were required to inhibit thymidine uptake. Lower doses of adenosine and cyclic AMP stimulated thymidine incorporation. The inhibition of thymidine uptake observed with millimolar concentrations of adenosine was independent of the type of mitogen (pokeweed or Con A), the concentration of mitogen, or the medium used, but could be increased if the cells were cultured in a serum with reduced levels of adenosine deaminase. Washout experiments failed to demonstrate a critical period early in immune induction during which adenosine exerted its inhibitory effects. Noninhibitory doses of EHNA potentiated the effects of adenosine and cyclic AMP on leucine and thymidine uptake. EHNA at a concentration of 50 muM also potentiated the inhibitory effects on thymidine uptake of dibutyryl cyclic AMP, butyric acid, norepinephrine, and isoproterenol, but not theophylline. When mitogenesis was assayed by leucine incorporations, no synergy between EHNA and these compounds was apparent. Uridine relieved to some extent the inhibition of blastogenesis produced by adenosine and cyclic AMP, but not by dibutyryl cyclic AMP, norepinephreine, isoproterenol, or theophylline. Neither uridine alone nor uridine plus adenosine protected lymphocytes from the inhibitory effects of EHNA.
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PMID:Effect of adenosine deaminase inhibition upon human lymphocyte blastogenesis. 17 77

The effect of adenosine on the mitogenic response of peripheral blood lymphocytes (PBL) and on the nucleotide pools of erythrocytes from normal horses, horses heterozygous for the combined immunodeficiency (CID) trait (carriers), and foals with CID was studied. When PBL from normal, carrier, and CID horses were stimulated by phytohemagglutinin (PHA), concanavalin A, or pokeweed mitogen, [3H]thymidine uptake was inhibited by adenosine (0.1 microM) to 1.0 mM) in a dose-dependent manner. Adenosine (100 microM) mediated inhibition of [3H]thymidine uptake was prevented in both normal and carrier horse PBL by incubation with uridine. Uridine had no sparing effect on PBL from horses with CID. Differences were detected between human and horse PBL in response to adenosine and erythro-9(2-hydroxy-3-nonyl) adenine (EHNA), a competitive inhibitor of adenosine deaminase. In the first assay, mitogen-stimulated PBL from horses were more sensitive to adenosine. In the second assay, adenosine was added to PBL cultures at various times after PHA addition. Adenosine inhibited mitogenesis in horse PBL if added within the first 24 h. In human PBL cultures, adenosine inhibited mitogenesis only if added within the first 4 h. The third assay measured capacity of PHA-stimulated human and horse lymphocytes to escape inhibition by adenosine or EHNA. At the end of a 72-h culture period, horse PBL were still inhibited of mitogenesis in both human and horse PBL. With prolonged incubation (72 h), synergistic inhibition was detected only in horse PB. With high-pressure liquid chromatography, nucleotide levels in erythrocytes of normal, carrier, and CID horses were found to be similar. Incubation with adenosine produced a 1.5- to 2-fold increase in total adenine nucleotide pools in erythrocytes from all horses. However, these increases were accompanied by alterations in the relative amounts of the nucleotide components. This was seen as a significant decrease in the ATP:(AMP plus ADP plus ATP) ratio and energy charge in erythrocytes from normal horses. In contrast, the ATP:(AMP plus ADP plus ATP) ratio decreased only slightly in erythrocytes from CID horses, whereas no change in the energy charge was detected. The data from these studies indicate a difference in adenosine metabolism exists between human and horse lymphoyctes, and an abnormality may exist in purine metabolism or in an interconnecting pathway in horses with CID.
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PMID:In vitro of adenosine on lymphocytes and erythrocytes from horses with combined immunodeficiency. 44 64

The metabolic and growth inhibitory effects of adenosine toward the human lymphoblast line WI-L2 were potentiated by the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and coformycin. EHNA, 5 micron, or coformycin, 3.5 micron, at concentrations that inhibited adenosine deaminase activity more than 90% had little effect on cell growth or the metabolic parameters studied. Adenosine, 50 micron, plus EHNA, 5 micron, arrested cell growth in both parent and adenosine kinase-deficient lymphoblasts, implicating the nucleoside as the mediator of the cytostatic effect. Adenosine, 50 micron, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90%, and reduced pyrimidine ribonucleotide concentrations. Uridine, 10 or 100 micron, reversed adenosine plus EHNA growth inhibition in WI-L2 but not in adenosine kinase mutants. Adenine, 500 micron, which may be converted to the same intracellular nucleotides as adenosine, reduced the growth rate by 50% in both parent and adenine phosphoribosyltransferase-deficient lymphoblasts. Although adenine also depleted cells of 5-phosphoribosyl-1-pyrophosphate and reduced pyrimidine ribonucleotide by 50%, the mechanisms of adenine and adenosine toxicity differ. In contrast to the ability of uridine to reverse adenosine cytostasis, growth inhibition by adenine was not reversed by uridine, indicating that pyrimidine ribonucleotide depletion is not the primary mechanisms of adenine toxicity.
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PMID:Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts. 66 33

Adenosine transport has been further characterized in rat renal brush-border membranes (BBM). The uptake shows two components, one sodium-independent and one sodium-dependent. Both components reflect, at least partly, translocation via a carrier mechanism, since the presence of adenosine inside the vesicles stimulates adenosine uptake in the presence as well as in the absence of sodium outside the vesicles. The sodium-dependent component is saturable (Km adenosine = 2.9 microM, Vmax = 142 pmol/min per mg protein) and is abolished at low temperatures. The sodium-independent uptake has apparently two components: one saturable (Km = 4-10 microM, Vmax = 174 pmol/min per mg protein) and one non-saturable (Vmax = 3.4 pmol/min per mg protein, Km greater than 2000 microM). Inosine, guanosine, 2-chloroadenosine and 2'-deoxyadenosine inhibit the sodium-dependent and -independent transport, as shown by trans-stimulation experiments, probably because of translocation via the respective transporter. Uridine and dipyridamole inhibited only the sodium-dependent uptake. Other analogs of adenosine showed no inhibition. The kinetic parameters of the inhibitors of the sodium-dependent component were further investigated. Inosine was the most potent inhibitor with a Ki (1.9 microM) less than the Km of adenosine. This suggests a physiological role for the BBM ecto-adenosine deaminase (enzyme which extracellularly converts adenosine to inosine), balancing the amount of nucleoside taken up as adenosine or inosine by the renal proximal tubule cell.
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PMID:Further characterization of adenosine transport in renal brush-border membranes. 235 78

Neplanocin A is a naturally occurring carbocyclic analog of adenosine which contains a cyclopentene moiety in place of ribose and has demonstrated antitumor and antimicrobial activity. This compound was highly toxic to Chinese hamster ovary (CHO) cells; the approximate minimum inhibitory concentration of neplanocin A for inhibition of clone formation was 0.1 microM. The toxicity of the agent was greatly reduced by prior treatment with adenosine deaminase. [3H]Uridine incorporation into perchloric acid insoluble material in growing cells was inhibited by neplanocin A more dramatically than that of [3H]thymidine or [3H]leucine. Treatment with the drug resulted in a marked depression of ATP pool levels. High pressure liquid chromatographic analysis of cellular nucleotide pools from cells treated with neplanocin A revealed the formation of an apparent drug metabolite (NpcTP) that eluted in the triphosphate region of the chromatographic profile. Treatment of NpcTP with alkaline phosphatase produced a nucleoside with properties similar to neplanocin A. An adenosine-kinase-deficient cell line formed little, if any, NpcTP but demonstrated only slight resistance to the agent. These observations suggest that neplanocin A was efficiently metabolized to the triphosphate level but that this metabolite was responsible for only a fraction of the observed toxicity.
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PMID:Metabolism and action of neplanocin A in Chinese hamster ovary cells. 240 84

The following evidence suggests that inhibition of hepatoma cell (HTC) growth by cyclic nucleotides is an adenosine-like effect that is greatly modified by the type and treatment of serum used in the culture medium and is probably not mediated by cyclic AMP-dependent protein kinase: 1) Heating serum reduces its phosphodiesterase content, thereby slowing metabolism of cyclic AMP and reducing the inhibition of HTC cell growth by cyclic AMP; 2) Using medium that contains phosphodiesterase but lacks adenosine deaminase causes adenosine to accumulate from cyclic AMP and increases the toxicity of cyclic AMP; 3) Uridine or cytidine reverses the growth inhibition caused by adenosine, 5'-AMP or cyclic AMP; 4) adenosine, 5'-AMP and N6-(delta 2-isopentenyl) adenosine are more toxic for HTC cells than is cyclic AMP, and N6,O2-dibutyryl cyclic AMP is not toxic; and 5) N6,O2'-dibutyryl cyclic AMP inhibits growth of Reuber H35 cells, but uridine prevents this inhibition of growth. We conclude that most, if not all, of the inhibitory effects of cyclic AMP and N6,O2'-dibutyryl cyclic AMP on HTc and Reuber H35 hepatoma cell growth are due to the generation of toxic metabolites.
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PMID:Inhibition of hepatoma cell growth by analogs of adenosine and cyclic AMP and the influence of enzymes in mammalian sera. 612 49

The mechanism of action of the adenosine analog, neplanocin A (NPC), was investigated in human colon carcinoma cell line HT-29. Cell viability was reduced to 38 and 17% of control by 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. Cytocidal activity was not affected by inhibition of adenosine deaminase with 2'-deoxycoformycin. Concomitant with decreased cell viability was the reduced incorporation of [14C]dThd and [3H]Leu, and to a lesser extent [3H]Urd, into acid-precipitable material. Labeling of rRNA and tRNA during drug treatment for 24 h with [methyl-3H]Met and [14C]Urd revealed that NPC primarily inhibited RNA methylation, and to a lesser extent, RNA synthesis. RNase T2 digests of total RNA indicated that base and 2'-O-methylation were inhibited to approximately the same degree. Metabolites of NPC were measured by reverse-phase high-performance liquid chromatography and it was found that the major drug metabolite was the drug analog of S-adenosylmethionine with little formation of the respective, S-adenosylhomocysteine metabolite. NPC was utilized to a very small degree for RNA synthesis where only 2 and 30 pmol of NPC/A260 were incorporated into rRNA and tRNA after 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. These results indicate that NPC is metabolized to a metabolite of S-adenosylmethionine which is a poor methyl donor for RNA methyltransferases, and that the accompanying decrease in RNA methylation and protein synthesis appears to be related to its cytocidal activity.
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PMID:Neplanocin A. A cyclopentenyl analog of adenosine with specificity for inhibiting RNA methylation. 633 23

We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As measured by the inhibition of thymidine or leucine incorporation, adenosine was more toxic to chronic lymphocytic leukemia (CLL) than to normal lymphocytes. This difference was not affected by the removal of adherent cells. The patients' B lymphocytes were more susceptible to adenosine toxicity than normal B lymphocytes. Similar responses were noted in T lymphocytes from both sources. Differential susceptibility was also observed with deoxyadenosine and adenosine analogues, including 5'deoxyadenosine. Uridine rescue from adenosine toxicity was observed for normal and CLL lymphocytes. In the presence of uridine, there was no difference in the residual inhibition of CLL as compared to normal lymphocytes. Intact CLL lymphocytes metabolized 14C-adenosine at a much lower rate than normal lymphocytes. While it appears that the greater toxicity of adenosine to CLL lymphocytes reflects the impaired catabolism of this nucleoside by these cells, evidence is presented that this is not the only mechanism underlying the differential susceptibility. These results may serve as the basis for further pharmacologic investigations of adenosine and adenosine deaminase inhibitors in chronic lymphocytic leukemia.
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PMID:Adenosine and adenosine analogues are more toxic to chronic lymphocytic leukemia than to normal lymphocytes. 660 34

Relative to lymphoid cells and normal fibroblasts, mouse melanoma cells (B16) were moderately sensitive to adenosine, with 80% growth inhibition being observed at 50 micro M adenosine instead of at 5 micro M as was reported with lymphoid cells or 400 micro M as was reported for normal fibroblasts. These differences were not due to adenosine deaminase because lymphoid cells had two to four times more of this activity than did melanoma cells or normal fibroblasts. In melanoma cells, complete adenosine-induced growth inhibition was a gradual process which was observed only after one to two population doublings; after 4 days of treatment, complete recovery was gradual requiring 48 hr. N6,O2-Dibutyryladenosine-cyclic-3':5' phosphate and polyadenylic acid were ineffective as growth inhibitors, whereas guanosine exhibited potent growth-inhibiting properties. Homocysteine thiolactone enhanced the cytotoxicity of adenosine but not guanosine; adenosine relieved the cytotoxicity of guanosine. These observations indicated that the two purine nucleosides were exerting their growth-inhibiting effects by different mechanisms. Uridine did not relieve adenosine-induced cytostasis, but at 50 micro M adenosine enhanced the incorporation of [3H]uridine into RNA. This suggested that the uridine phosphate pools were depleted at low adenosine concentrations and that exogenous adenosine influences the availability of pyrimidines.
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PMID:Characterization of adenosine-induced cytostasis in melanoma cells. 738 82


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