Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of myocardial adenosine kinase (E.N. 2.7.1.20) in a number of species was assayed. Rat heart contained the highest specific activity. From this source adenosine kinase was purified in a simple way 80-fold, until it was free of adenosine deaminase activity. A molecular weight of about 39 000 was measured. NSC 113939 (1), NSC 113940 and 8-azaadenosine inhibited myocardial adenosine kinase. Dipyridamole stimulated the enzyme at high adenosine levels, and inhibited at low substrate concentrations. A number of divalent cations could (partially) substitute for Mg2+. The optimal concentration of MgCl2 or MnCl2 was about 0.5 mM; concentrations exceeding 1 mM inhibited severely. An apparent Km for ATP of 0.1 mM was measured, whereas an apparent Km for adenosine of 0.5 muM was was found. The latter increased to 3.3 muM, when dipyridamole was added. Replacement of ATP by GTB or ITP increased the activity, and UTP and CTP were inferior as a phosphate donor.
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PMID:Partial purification and properties of rat-heart adenosine kinase. 7 32

T-cell acute lymphoblastic leukemia is an aggressive disease that responds poorly to "standard" therapy designed for the more common B-lineage ALLs in childhood. The principles of this "standard" therapy were derived from empiric clinical trials. Thus, it is not surprising that the therapy that had the greatest impact on survival in the group as a whole would be found to be most successful for the most common subset of patients. T-cell malignant lymphoblasts share many biologic features that set them apart from the more common B-lineage lymphoblasts. Some of these biologic features suggest therapeutic approaches that should be particularly successful in treating patients with T-cell leukemia. The use of aggressive, multiple-agent "pulse" chemotherapy has been shown through empiric trials to have relative efficacy in T-cell lymphoblastic leukemia, presumably because of the rapid generation time and high growth fraction. Future studies will (1) determine the optimal dose and schedule of cytosine arabinoside needed to exploit the increased Ara-CTP accumulation in T-cell blasts, (2) determine the efficacy of a new agent, deoxycoformycin, an inhibitor of adenosine deaminase, to exploit the biochemical phenotype of T-cell blasts, and (3) assess the ability of conjugated anti-T monoclonal antibodies to deliver a cytotoxic agent, thus exploiting unique antigenic determinants at the cell surface. As more is learned about the biology of T-cell malignancies, further treatment strategies may be suggested to exploit the new features that are discovered. Similarly, it is hoped that the unique features of the B-lineage leukemias will suggest treatment strategies that will improve survival in those patients as well. Certainly, improved survival has already been achieved in the case of the B-cell leukemias and Burkitt's lymphomas, and improvement may also be possible for the pre-B and early pre-B phenotypes of lymphoblastic leukemia.
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PMID:Treatment of T-lineage acute lymphoblastic leukemia. 226 86

The exact role of adenosine in the adenosine deaminase (EC 3.5.4.4) deficiency-related severe combined immunodeficiency disease has not been ascertained. We analysed the effects of adenosine, in the presence of the adenosine deaminase inhibitor, deoxycoformycin, on cell growth, cell phase distributions and intracellular nucleotide concentrations of cultured human lymphoblasts. Adenosine had a biphasic effect on cell growth and cell cycle distribution of a partial hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) deficient MOLT-HPRT cell line. After 24 h of incubation, 60 microM adenosine inhibited cell growth more extensively than did 100 and 200 microM adenosine. The distribution of the MOLT-HPRT cells in the various phases of the cell cycle showed a similar biphasic pattern. Adenosine concentrations in the medium below 10 microM caused accumulation of adenine ribonucleotides and depletion of phosphoribosylpyrophosphate, UTP and CTP in the cells. This was associated with inhibition of cell growth. Medium adenosine concentrations above 10 microM neither resulted in accumulation of adenine ribonucleotides nor in inhibition of cell growth.
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PMID:Inhibition of lymphoid cell growth by adenine ribonucleotide accumulation. The role of phosphoribosylpyrophosphate-depletion induced pyrimidine starvation. 243 39

Biochemical impairments in spleen immunocompetent cells (T- and B-lymphocytes) were revealed in host (C3HA mice) of transplantable and ortoaminoazotoluol-induced hepatomas in the course of their growth. As soon as hepatoma emerged (chemical carcinogenesis), the activity of adenosine deaminase and purine nucleoside phosphorylase in T- and B-lymphocytes were found to be reduced 2-6 and 7-10-fold, respectively in parallel with the impairment of their immune system. These alterations were accompanied by the increase in concentrations of dGTP in T-lymphocytes (5.4-fold) and of dATP in B-lymphocytes (4-fold) as well as with the inhibition of DNA synthesis, predominantly in T-lymphocytes. In both T- and B-lymphocytes, the dCTP pool was decreased. In the spleen, T- and B-lymphocytes of mice carrying transplantable 22 hepatoma 22 by the moment of its maximal growth (5th day), the DNA synthesis was inhibited as revealed by the reduction of (a) thymidine kinase activity, (b) rate of the labeled thymidine incorporation into DNA, and (c) intracellular dTTP and dCTP concentrations. In latter periods (from 8th day up to the moment of death), drastic stimulation of DNA synthesis in spleen T- and B-lymphocytes was observed irrespective of the impairments in the immune function and the decrease of the adenosine deaminase activity. In the course of growth of both transplantable and induced solid hepatomas in host spleen T- lymphocytes, the activity of the CTP-dependent thymidine kinase isoenzyme increased, coinciding in time with the activation of antigen-specific T-suppressors in the same organ.
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PMID:[Changes in DNA and purine nucleotide synthesis in lymphoid cells and sensitivity to glucocorticoids associated with the impairment of differentiation and immune function in mice during tumor growth. Spleen T- and B-lymphocytes]. 308 34

After four days of treatment with 10(-8) M TPA, differentiation of the human T-lymphoblastoid cell line MOLT-4 was induced along the T cell lineage, confirmed by a fall in adenosine deaminase and 5'-ectonucleotidase and a rise in purine nucleoside phosphorylase activity. TPA-treated cells became resistant to the cytotoxic effects of 1-beta-D-arabinofuranosylcytosine (Ara-C), 9-beta-D-arabinofuranosyladenine (Ara-A), and 2-chlorodeoxyadenosine. This was, in part, due to the altered cell cycle distribution (accumulation of cells in the G1 phase), since the toxicity of Ara-C and Ara-A is S phase specific. The diminished rate of Ara-C transport concomitant with Ara-CTP formation after TPA treatment is considered to be the biochemical basis for this acquired resistance.
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PMID:Changes in sensitivity to anticancer drugs during TPA-induced cellular differentiation in a human T-lymphoblastoid cell line (MOLT-4). 326 Jun 48

In thymocytes of C3HA mice carrying the transplantable and ortoaminoazotoluene induced hepatomas at the time of their intense growth a drastic decrease in adenosine deaminase activity set in and 3-4-fold augmentation of intracellular concentration of dATP and dGTP, potential inhibitors of ribonucleoside diphosphate reductase was observed, leading to the reduction of the DNA synthesis. The latter event was evidenced by a suppressed 14C-thymidine incorporation into thymocytes DNA in vitro, decreased thymidine kinase activity, intracellular dTTP and depletion of dCTP pools. Only in the terminal period of hepatocarcinogenesis (12 months) a 4-fold increase in the corticosterone serum concentration was observed. As for the mice carrying transplantable 22a hepatoma, serum hormone levels augmented 4-fold as early as 24 h after tumor implantation and thereafter kept increased two fold. An elevated activity of terminal deoxynucleotidyl transferase in mouse thymocytes has been shown to be characteristic of the late periods of tumor growth reflecting the arrest of the immature cortical thymocyte differentiation. By the time hepatomas emerged in the course of hepatocarcinogenesis in spleen T and B lymphocytes a significant drop in the activity of adenosine deaminase (3-4-fold) and purine nucleoside phosphorylase (2-8-fold) was noted--the events directly correlated with the weakening of cell immune functions. The disorders described were accompanied by the accumulation of dGTP in spleen T lymphocytes, dATP in B lymphocytes and inhibition of DNA synthesis, predominantly in T lymphocytes. In the latter instance the pool of dCTP was found to be depleted. In spleen T and B lymphocytes of mice carrying solid 22a hepatoma when the peak of its growth was reached (day 5) the rate of DNA synthesis dropped. Later on (from day 8 to the animal death), however, in spite of the suppression of immune function and the decrease in adenosine deaminase activity a drastic stimulation of DNA synthesis in spleen T and B lymphocytes was observed. The increase in spleen T suppressor activity in the course of intense growth of the both types of hepatomas coincided in the time with the stimulation of the CTP-dependent thymidine kinase isoenzyme activity in total T lymphocyte population of the same organ.
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PMID:Some biochemical mechanisms underlying the impairment of T and B cell immunity in C3HA mice during hepatoma growth. 349 9

9-Deazaadenosine (c9Ado), a novel C-nucleoside, has been found to inhibit lymphocyte-mediated cytolysis (LMC) in a time-dependent manner. c9Ado inhibited LMC by 50% at concentrations of 10 and 0.07 microM after drug-pretreatment periods of 3 and 22 hr, respectively, although a 1-hr pretreatment of cytolytic lymphocytes with 100 microM c9Ado had no effect upon this lymphocyte function. c9Ado was metabolized rapidly and extensively to 9-deazaadenosine 5'-triphosphate (c9ATP) both by mouse cytolytic lymphocytes and by human erythrocytes. Adenosine kinase purified from rabbit liver phosphorylated c9Ado with a Km of 200 microM and a Vmax of 8% that for adenosine. The metabolic buildup of c9ATP in lymphocytes was accompanied by a large, time-dependent decrease in cellular ATP and by smaller percentage decreases in CTP, UTP and GTP. Among other biochemical effects examined, c9Ado was found to cause a decrease in lymphocyte cAMP content and appeared to be neither an inhibitor nor a substrate for S-adenosylhomocysteine hydrolase. Consistent with this latter result, L-homocysteine thiolactone had no effect on the inhibition of LMC by c9Ado. Neither the inhibition of LMC by c9Ado nor the metabolic formation of c9ATP in lymphocytes was affected by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), indicating that c9Ado is not a substrate for adenosine deaminase. 5-Iodotubercidin, a non-competitive inhibitor (Kis = 9 nM, Ku = 20 nM) of adenosine kinase, prevented the above effects of c9Ado on lymphocyte function, c9ATP formation, and ATP levels. Either complete preservation (with coformycin) or partial replenishment (with adenosine plus EHNA) of ATP levels in c9Ado-treated lymphocytes resulted in partial restoration of cytolytic function to cells containing large amounts of c9ATP. These results suggest that c9Ado is inhibitory to LMC both because it causes a decrease in the absolute concentration of ATP within the cytolytic lymphocytes and because it permits the establishment within these cells of an unfavorable c9ATP:ATP ratio which impedes the utilization of ATP in a reaction essential to the execution of this lymphocyte function.
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PMID:Inhibition of lymphocyte function by 9-deazaadenosine. 630 53

Nucleotides, nucleosides and purine bases in trichloroacetic acid extracts of freeze clamped samples of human placenta have been measured by high-pressure liquid chromatography. The concentrations of the nucleotides concerned with energy transduction, ATP, ADP and AMP, and especially the energy charge, are stable over periods of ischaemia of 30 min. Concentrations of 14 nucleotides, including UDPAG, GDP Man, UDP and CTP, have now been defined. In addition, the concentrations of hypoxanthine, xanthine, uridine, adenine and inosine are indicated. Concentrations of the vasodilator adenosine are similar to the apparent Michaelis constants of its main metabolizing enzymes adenosine kinase and adenosine deaminase. The availability of 'normal' values of adenine nucleotide concentrations in human placenta should permit the detection of 'placental insufficiency' of energy supply, if this condition exists.
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PMID:Nucleotide, nucleoside and purine base concentrations in human placentae. 707 37

The activation of P2-receptors has a wide range of diverse effects in many tissues. Here we show that extracellular ATP stimulates lipogenesis in adipocytes derived from the epididymal fat pads of male Wistar rats. The lipogenic effect of ATP is not susceptible to treatment of adipocytes with adenosine deaminase or an adenosine receptor antagonist. Degradation of ATP in adipocyte suspension by ectonucleotidases is slow and remaining ATP concentrations are sufficient to activate P2-receptors. ATP does not affect basal or insulin stimulated glucose transport, or basal or isoproterenol stimulated lipolysis, respectively. The lipogenic effect of ATP is mimicked by the adenine compounds, ADP, AMP, and beta,gamma-methylene-ATP, but not by other nucleotides (UTP, UDP, CTP, GTP, ITP, and diadenosine tetraphosphate), indicating that extracellular nucleotides stimulate lipogenesis via a P2-receptor. ATP and its receptor may define a signalling system in adipocytes, which regulates fat stores independently from established hormones.
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PMID:Stimulation of lipogenesis in rat adipocytes by ATP, a ligand for P2-receptors. 1535 93