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 rational design of antitumor and antiviral agents must ultimately take advantage of biochemical differences between normal host cells and transformed cells. The initial experiments must be performed with subcellular or cellular model systems. For the studies with arabinosyl nucleosides we have chosen those enzyme systems, synthesizing DNA and RNA; being precursor analogues, the different arabinosyl nucleosides have been added in the triphosphate state to the different DNA- and RNA polymerase assays. 1-beta-D-Arabinofuranosylcytosine-5'-triphosphate has been found to inhibit the RNA-dependent DNA polymerases (isolated from oncogenic RNA viruses) 200-fold more sensitively than viral and cellular DNA-dependent DNA polymerases. Recent results, showing that RNA-leukemia-virus-related sequences are present in DNA of some human leukemia patients might support the assumption that the efficacy of this antimetabolite in the treatment of acute leukemia is due to its, at least relative selective inhibitory activity on reverse transcriptase. 9-beta-D-Arabinofuranosyladenine-5'-triphosphate is a strong inhibitor of cellular DNA polymerases with the cytological consequence of an inhibition of cell proliferation. The clinical benefit of the compound in treatment of tumors is dependent on their levels of adenosine deaminase. The triphosphate of this compound is a 100-fold more sensitive inhibitor of the herpesvirus DNA polymerase compared to the cellular replicative DNA polymerase. In addition the analogue, incorporated into herpesvirus DNA, acts as chain terminator. These effects are the biochemical basis for the highly selective antiherpesvirus activity of this antimetabolite. The anomer 9-alpha-D-arabinofuranosyladenine-5'-triphosphate only inhibits cellular replicative DNA polymerase and has no effect on herpesvirus DNA polymerase. Consequently this agent acts only cytostatically and not antivirally. Concerning 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylthymine no pronounced antitumor or antiviral effect is known.
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PMID:Rational design of arabinosyl nucleosides as antitumor and antiviral agents. 61 2

1 The cardiovascular actions of 23 adenosine analogues have been examined in anaesthetized open thorax dogs; the analogues were substituted in the 2-position of the purine ring, or in the exocyclic amino group, or were modified in the imidazole or sugar rings.2 The effects of these compounds on coronary blood flow, peripheral blood pressure, and heart rate were compared with those of adenosine.3 9-beta-D-Arabinofuranosyladenine had no cardiovascular action; the other analogues on intra-atrial administration caused an immediate increase in coronary blood flow, the magnitude and duration of which varied with the structures of the analogues.4 2-Fluoro-, 2-bromo-, 2-isobutylthio-, 2-ethylamino-, and 5'-deoxy-5'-chloro- adenosines had coronary dilator potencies equal to or greater than that of adenosine. No relationship was found between the dilator potency of the adenosine analogues and their duration of coronary dilator action.5 The coronary dilator action of adenosine was potentiated by inosine, 9-beta-D-arabinofurano-syladenine, tubercidin, N(6)-methyladenosine and 2-trifluoromethyl-N(6)-methyladenosine.6 There was no correlation between the substrate specificities of the shorter-acting analogues for adenosine deaminase or adenosine kinase and their duration of coronary dilator action.7 It is proposed that in the anaesthetized dog, uptake into tissues is a more important mode of removal of adenosine and adenosine analogues from the vascular system than inactivation by adenosine deaminase, that the duration of coronary dilator action of the analogues is related primarily to their specificity for the carrier which mediates adenosine uptake, and that the adenosine carrier is not associated with kinase action.
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PMID:Studies on the coronary dilator actions of some adenosine analogues. 436 49

9-beta-D-Arabinofuranosyladenine (ara-A), 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate competitively inhibit both the synthesis and hydrolysis of S-adenosylhomocysteine catalyzed by S-adenosylhomocysteinase [S-adenosylhomocysteine hydrolase (EC 3.3.1.1)] from mouse liver, and the inhibitor constants were 5.0 X 10(-6), 1.1 X 10(-4), and 1.0 X 10(-3) M, respectively. A time-dependent inactivation of the enzyme was observed when the enzyme was preincubation with ara-A, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, or 9-beta-D-arabinofuranosyladenine 5'-triphosphate. ara-A was the most potent inactivator. The inactivation with ara-A was less pronounced in the presence of adenosine, S-adenosylhomocysteine, adenine, adenosine 5'-monophosphate, or adenosine 5'-diphosphate, showed first-order kinetics, saturability, and irreversibility. The rate of inactivation was half-maximal at 5 X 10(-6) M ara-A, and the rate constant of inactivation was 0.43 min-1 at saturating concentrations of ara-A. ara-A was tightly but not covalently bound to the enzyme. ara-A bound to the enzyme was not available for deamination to 9-beta-D-arabinofuranosylhypoxanthine catalyzed by the enzyme adenosine deaminase.
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PMID:Interaction of 9-beta-D-arabinofuranosyladenine, 9-beta-D-arabinofuranosyladenine 5'-monophosphate, and 9-beta-D-arabinofuranosyladenine 5'-triphosphate with S-adenosylhomocysteinase. 616 Sep 9

Adenine arabinoside (ara-A) at a concentration of 5-10 micrograms/ml inhibited the multiplication of two Epstein-Barr virus (EBV) producer lymphoblastoid cell lines B . 95-8 and P3HR-1. The nonproducer EBV genome carrier cell line, Raji, and the EBV negative cell line, Ramos, were not significantly affected. The cytotoxicity of ara-A to Ramos, Raji and P3HR-1 cells increased in the presence of 1 . 10(-5)M erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of adenosine deaminase. EHNA alone was noncytotoxic and even had a mild stimulatory effect on cell multiplication. The level of adenosine deaminase in Raji and Ramos cells was similar to that observed in human cord blood lymphocytes, as determined by starch gel electrophoresis. A low level of adenosine deaminase was detected in P3HR-1 cells and the enzyme was absent from B . 95-8 cells. These findings indicate that in the absence of adenosine deaminase, ara-A cytotoxicity increased. Ara-A (5 micrograms/ml) and EHNA (1 . 10(-5)M) had no effect on human cord blood lymphocytes stimulated by phytohemagglutinin as measured by (3H) thymidine uptake, but had some effect on protein A-stimulated lymphocytes. Ara-A, however, inhibited the transformation of human cord blood lymphocytes by EBV, which EHNA did not inhibit. The synthesis of EBV capsid antigen in B . 95-8 cells was also inhibited by ara-A and slightly stimulated by EHNA.
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PMID:Cytotoxicity of arabinofuranosyladenine and erythro-9-(2-hydroxy-3-nonyl) adenine to Epstein-Barr virus producer and nonproducer lymphoma cells in culture. 630 55

9-beta-D-Arabinofuranosyladenine (ara-A) inactivates isolated S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) as well as AdoHcy hydrolase in intact cells. Whereas the inactivation in cell-free systems is an irreversible process, the AdoHcy hydrolase activity in rat hepatocytes exposed to ara-A gradually recovered upon prolonged incubation of the cells in a medium devoid of ara-A. This process, tentatively termed reactivation of the enzyme, was nearly totally dependent on a high level of adenosine deaminase in the extracellular medium, which induced a decrease in intracellular content of adenosine as well as ara-A. Reactivation of intracellular enzyme was inhibited by adenosine deaminase inhibitors [2'-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine] and the synthetic substrate for AdoHcy hydrolase, 3-deazaadenosine. An inhibitor of protein synthesis (cycloheximide) was without effect. Homocysteine, which protected the intracellular AdoHcy hydrolase against inactivation by ara-A, induced no reactivation of the enzyme. The half-life of the intracellular ara-A-AdoHcy hydrolase complex was about 90 min and was not affected by adenosine deaminase, 3-deazaadenosine, or homocysteine added to the cell suspension. However, the rate of elimination of the complex in the hepatocytes exceeded the rate of reactivation of AdoHcy hydrolase. Thus, the elimination process accounted for the reactivation, but not correlation between these two processes was observed. Reactivation of intracellular AdoHcy hydrolase caused a pronounced fall in cellular content of AdoHcy. The possibility that reduced cellular level of AdoHcy induced the reactivation of AdoHcy hydrolase seemed unlikely. This statement was based on the observation that reactivation was observed also under conditions of high concentrations of AdoHcy (obtained by the addition of homocysteine to the cell suspension). Reactivation of AdoHcy hydrolase with a concomitant decrease in cellular level of AdoHcy could also be demonstrated with mouse plasmacytoma (MPC-11) cells and mouse fibroblasts (L-929) exposed to ara-A, but the reactivation process was far less pronounced than with hepatocytes.
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PMID:Reactivation of S-adenosylhomocysteine hydrolase activity in cells exposed to 9-beta-D-arabinofuranosyladenine. 697 84