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)

The cytotoxic effects of the adenosine deaminase resistant analogues 2-bromo-2'-deoxyadenosine (2-BrdAdo) and 2-chloro-2'-deoxyadenosine (2-CldAdo) have been compared with those of deoxyadenosine (dAdo). Like 2-CldAdo, 2-BrdAdo is highly effective in inhibiting the growth of many T-lymphoblastoid, B-lymphoblastoid, and myeloid cell lines in culture. Concentrations required to inhibit growth of CCRF-CEM human T-lymphoblastoid cells by 50% (IC50) are: 2-CldAdo, 0.045 microM; 2-BrdAdo, 0.068 microM; dAdo, 0.9 microM in the presence of 5 microM erythro-9-(2-hydroxy-3-nonyl)adenine. Like dAdo, 2-BrdAdo causes a much greater decrease in DNA synthesis than in RNA and protein synthesis. For each of the nucleosides the concentration required to cause 50% inhibition of DNA synthesis (as measured by thymidine incorporation) in an 18-h exposure is very similar to the IC50 for growth and to the concentration required to decrease viability (clonogenicity) over 18 h by 50% (EC50). A fraction of CCRF-CEM cells (approximately equal to 30%) is resistant to killing by exposure to 2-BrdAdo or 2-CldAdo for 4 h at concentrations 100 times the EC50, but 3% of cells are resistant to exposure for 4 h to a concentration of dAdo 3 times the EC50. Each of the three nucleosides causes accumulation of cells in S phase, the accumulation becoming more marked with longer periods of exposure and with higher concentrations of nucleoside. During exposures for 18-24 h at a concentration of nucleoside near the EC50 most cells accumulate in S, with most in early S, whereas exposure to concentrations greater than EC95 accumulates cells at the G1/S border. This suggests that loss of viability is associated with a blockade of some process specifically occurring at the initiation of S phase. At an optimum dosage schedule, 2-BrdAdo and 2-CldAdo have similar therapeutic effects against L1210 in vivo, both producing over 99% cell kill, but the optimum dosage of 2-CldAdo is lower.
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PMID:Effects of cytotoxicity of 2-chloro-2'-deoxyadenosine and 2-bromo-2'-deoxyadenosine on cell growth, clonogenicity, DNA synthesis, and cell cycle kinetics. 242 77

2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. The complex between adenosine deaminase and 2'-chloropentostatin dissociated with a half-life of approximately 3 hr, compared with 68 hr for the complex between adenosine deaminase and pentostatin. 2'-Chloropentostatin, at concentrations up to 10 micromolar, did not cause significant inhibition of growth of WI-L2 human B-cell lymphoblasts, or of CCRF-CEM human T-cell lymphoblasts in culture. However, it greatly potentiated the inhibitory potency of adenosine, 2'-deoxyadenosine, or arabinosyladenine towards these cell lines. This potentiating effect was equipotent for 2'-chloropentostatin and pentostatin. T-cells (CCRF-CEM) were much more sensitive to the inhibitory effect of combinations of adenosine or 2'-deoxyadenosine with 2'-chloropentostatin or pentostatin than were B-cells (WI-L2). Pentostatin and 2'-chloropentostatin had no significant antitumor activity against mouse leukemia L1210 in vivo. However, these adenosine deaminase inhibitors, at nontoxic doses, greatly potentiated the antitumor activity of ara-A 5'-phosphate. 2'-Chloropentostatin was somewhat more active in this regard than was pentostatin.
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PMID:The biochemical pharmacology of (2'-R)-chloropentostatin, a novel inhibitor of adenosine deaminase. 243 5

We studied the effects of adenosine and adenosine derivatives on adenylate cyclase activity in cultured endothelial cells from bovine pulmonary artery. Basal and stimulated enzyme activities were measured in membrane preparations using [alpha-32P]ATP as the substrate and chromatographic isolation of formed [32P]cAMP. Basal cyclase activity was 11 +/- 1 (mean +/- SEM) pmol/mg protein/min. Forskolin, 5'-guanylylimidodiphosphate (Gpp(NH)p) and (-)isoproterenol stimulated adenylate cyclase in a concentration-dependent manner, producing maximal stimulations of three, seven and four times the basal activity respectively. In the presence of adenosine deaminase, cyclohexyladenosine, an A1 agonist, had no effect on basal and forskolin- or Gpp(NH)p-stimulated activities, whereas 5'-(N-ethyl)-carboxamidoadenosine (NECA), an A2 agonist, had a small stimulatory effect (52% increase over basal). In the presence of IBMX, adenosine and two P-site agonists, 2',5'-dideoxyadenosine (DDA) and 2'-deoxyadenosine-3'-monophosphate (2'-deoxy-3'-AMP), inhibited forskolin (30 microM)-stimulated adenylate cyclase activity with an order of potency of 2'-deoxy-3'-AMP greater than DDA greater than adenosine. DDA and 2'-deoxy-3'-AMP were also able to inhibit cyclase activity stimulated by Gpp(NH)p (10(-5)M) or isoproterenol (10(-6)M) with the same order of potency. Only 2'-deoxy-3'-AMP inhibited the stimulated adenylate cyclase activity by more than 50% (IC50 = 19-32 microM). These findings indicate that (1) long-term cultured endothelial cells from bovine pulmonary artery express A2 and beta-adrenergic receptors which stimulate adenylate cyclase activity through Gs transducer proteins, and (2) the natural compound and P-site agonist, 2'-deoxy-3'-AMP, is a potent inhibitor, and possibly a natural regulator, of adenylate cyclase activity in this tissue.
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PMID:Modulation of adenylate cyclase activity in cultured bovine pulmonary arterial endothelial cells. Effects of adenosine and derivatives. 246 5

We have established long term cell lines from a patient with adenosine deaminase (ADA)-deficient severe combined immunodeficiency by stimulation of blood and bone marrow cells with PHA and IL-2 followed by transformation of the activated cells with the human retrovirus HTLV-I. Despite the absence of detectable T cells in the patients blood, cell lines grew that carried the phenotype of mature activated T cells. TJF-2, the line established from blood, was characterized in detail. The concentration of ADA in TJF-2 cells was less than 1% of normal (3.2 U vs 413.0 U). Studies with pharmacologic inhibitors of ADA suggest that the residual adenosine deaminating activity of TJF-2 is from an enzyme distinct from true ADA, a nonspecific aminohydrolyase. Growth of TJF-2 cells was hypersensitive to inhibition by 2'-deoxyadenosine compared to normal T cells (ID50, 55 microM vs greater than 1000 microM). Analysis of 2'-deoxyadenosine-challenged cells showed that TJF-2 cells accumulated significant levels of deoxyadenosine triphosphate, whereas normal T cells did not unless they were also incubated with the ADA inhibitor deoxycoformycin. Southern and Northern blot analysis of these cells revealed a grossly intact ADA gene that produced a normal size ADA mRNA. Yet, despite ADA deficiency, cells of the TJF-2 line were otherwise indistinguishable from HTLV-I-transformed T cells derived from normal donors with respect to dependence on exogenous IL-2 for growth, clonal rearrangement patterns of TCR beta-chain genes, response to PHA, and rapid restoration of cellular volume after hypotonic challenge. The TJF-2 line thus represents a unique HTLV-I-transformed human T cell line exhibiting ADA deficiency and its expected metabolic consequences.
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PMID:Establishment and characterization of adenosine deaminase-deficient human T cell lines. 249 84

B-lymphoblastoid cell lines (LCL) transformed by Epstein-Barr virus (EBV) were established from a patient with severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency, from his mother and from a normal volunteer. ADA activities of the patient's and mother's LCL were about 0.5% and 25% of that of the normal LCL, respectively. Proliferation of these three LCL was related to the ADA activity. The patient's LCL grew well in medium containing fetal bovine serum (FBS), but slowly in medium with the ADA inhibitor 2'-deoxycoformycin-treated FBS, horse serum, or without serum. Proliferation of the patient's LCL was markedly inhibited in serum-free medium containing 2'-deoxyadenosine.
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PMID:Comparative characterization of B-lymphoblastoid cell lines in adenosine deaminase deficiency and its heterozygote. 261 47

1. The adenosine deaminase (ADA) activities of chicken erythrocyte and heart cytosols had pH optima of 6.5. The temperature optima for erythrocyte and heart ADA were 30 and 35 degrees C, respectively. 2. The deoxyadenosine/adenosine deamination ratios ranged from 0.75 to 0.84 for both ADA activities. 3. For erythrocyte ADA, Km values were 8.9-12.9 microM adenosine (range) and 8.3 microM 2'-deoxyadenosine. For heart ADA, Km values were 6.7-12.0 microM adenosine (range) and 5.3 microM 2'-deoxyadenosine. 4. Inosine was a competitive inhibitor of both erythrocyte (Ki = 73 microM) and heart (Ki = 109 microM) ADA.
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PMID:Adenosine deaminase activity of chicken erythrocyte and heart cytosols. 279 50

Theophylline inhibits basal adenylate cyclase activity as well as cyclase stimulated by sodium chloride, sodium fluoride, GTP or 5'-guanylimidodiphosphate. This inhibition, is dose-dependent and shows non-competitive inhibition, with respect to MgATP. The presence of adenosine deaminase does not alter the effect of theophylline. The inhibition produced by theophylline is not additive with that due to 2'-deoxyadenosine 3'-monophosphate (a P-site agonist). It is suggested that theophylline may act at the P-site to reduce adenylate cyclase activity.
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PMID:Inhibition of rabbit cardiac adenylate cyclase by theophylline. 286 8

Several B lymphoblastic cell lines are known to be relatively resistant to the combination of 2'-deoxyadenosine with an adenosine deaminase inhibitor. These cell lines are believed to have a greater capacity to dephosphorylate 2'-deoxyadenosine nucleotides, thus preventing excessive accumulation of potentially toxic metabolites. In this study, the 2'-deoxynucleoside 5'-monophosphate dephosphorylating activities of human peripheral lymphocytes were examined. Peripheral lymphocytes have at least three nucleotide 5'-monophosphate nucleotidases distinguished by different pH optimums, substrate preference, Mg2+ requirement, inhibitors, and molecular weights. Two of the enzymes appeared to be cytosolic, only one of which had significant substrate activity with dAMP. This enzyme had an acidic pH optimum (5.0), no Mg2+ requirement, was inhibited by tartrate, and demonstrated broad substrate specificity. The other cytosolic nucleotidase required Mg2+, had a pH optimum of 5.5 to 6.0, was activated by 2'-deoxyinosine, and demonstrated a substrate preference for 3'- and 5'-monophosphate 2'-deoxynucleosides of hypoxanthine, guanine, uracil, and thymine. The third enzyme, ecto 5'-nucleotidase, is associated with the cell membrane. Although the ecto 5'-nucleotidase activity was higher in the B lymphocytes, the cytosolic nucleotidases were similar in activity in the T and B lymphocytes.
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PMID:Nucleotidase activities of human peripheral lymphocytes. 299 75

Adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) from Bacillus cereus NCIB 8122 has been purified to electrophoretic homogeneity by ammonium sulfate precipitation, gel filtration through Sephadex G-100, DEAE-Sephadex A-50 chromatography and ion-exchange HPLC on DEAE-Polyol. The enzyme activity is stabilized (at temperatures from 0 degrees C to 40 degrees C) by 50 mM NH4+ or K+, while it is irreversibly lost in the absence of these or a few other monovalent cations. Glycerol (24% by volume) helps the cation in stabilizing the enzyme activity above 40 degrees C, but also exerts per se a noticeable protecting effect at room temperature. B. cereus adenosine deaminase displays the following properties: Mr on Sephadex G-200, 68,000; Mr in SDS-polyacrylamide gel electrophoresis, 53,700; optimal pH-stability (in the presence of 50 mM KCl) over the range 8-11 at 4 degrees C, and maximal catalytic activity at 30 degrees C between pH 7 and 10; Km for adenosine around 50 microM over the same pH range and Km for 2'-deoxyadenosine around 400 microM.
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PMID:Purification, stability and kinetic properties of highly purified adenosine deaminase from Bacillus cereus NCIB 8122. 309 80

The simultaneous administration of 3'-deoxyadenosine N1-oxide (3'-dANO) and the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) or 2'-deoxycoformycin (2'-dCF) to mice bearing Ehrlich ascites tumor cells resistant to 3'-dANO resulted in 80%-90% inhibition of tumor growth in vivo. 3'-dANO and 2'-dCF increased the survival time of tumor-bearing mice by a factor of 2. In vitro studies showed that the 3'-dANO resistant Ehrlich cells initiate the metabolism of 3'-dANO by a reduction to 3'-deoxyadenosine, which is converted primarily to 3'-deoxyinosine by adenosine deaminase and, to a small extent, phosphorylated to the cell toxic agent 3'-dATP. By the addition of EHNA or 2'-dCF it was possible to block the formation of 3'-deoxyinosine, resulting in a profound stimulation in the accumulation of 3'-dATP. The development of resistance to 3'-dANO was studied in cell cultures and found to be accompanied by changes in the enzyme activities of the reductase, the adenosine kinase, and the adenosine deaminase.
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PMID:Synergistic effect of 3'-deoxyadenosine N1-oxide and adenosine deaminase inhibitors on growth of Ehrlich ascites tumor cells in vivo. 325 21


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