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)

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

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

The effects of adenosine were studied on human neutrophils with respect to their generation of superoxide anion, degranulation, and aggregation in response to soluble stimuli. Adenosine markedly inhibited superoxide anion generation by neutrophils stimulated with N-formyl methionyl leucyl phenylalanine (FMLP), concanavalin A (Con A), calcium ionophore A23187, and zymosan-treated serum; it inhibited this response to PMA to a far lesser extent. The effects of adenosine were evident at concentrations ranging from 1 to 1,000 microM with maximal inhibition at 100 microM. Cellular uptake of adenosine was not required for adenosine-induced inhibition since inhibition was maintained despite the addition of dipyridamole, which blocks nucleoside uptake. Nor was metabolism of adenosine required, since both deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl) adenine did not interfere with adenosine inhibition of superoxide anion generation. The finding that 2-chloroadenosine, which is not metabolized, resembled adenosine in its ability to inhibit superoxide anion generation added further evidence that adenosine metabolism was not required for inhibition of superoxide anion generation by neutrophils. Unexpectedly, endogenously generated adenosine was present in supernatants of neutrophil suspensions at 0.14-0.28 microM. Removal of endogenous adenosine by incubation of neutrophils with exogenous adenosine deaminase (ADA) led to marked enhancement of superoxide anion generation in response to FMLP. Inactivation of ADA with DCF abrogated the enhancement of superoxide anion generation. Thus, the enhancement was not due to a nonspecific effect of added protein. Nor was the enhancement due to the generation of hypoxanthine or inosine by deamination of adenosine, since addition of these compounds did not affect neutrophil function. Adenosine did not significantly affect either aggregation or lysozyme release and only modestly affected beta-glucuronidase release by neutrophils stimulated with FMLP. These data indicate that adenosine (at concentrations that are present in plasma) acting via cell surface receptors is a specific modulator of superoxide anion generation by neutrophils.
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PMID:Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. 631 34

The antiherpes activities of erythro- and threo-9-(2-hydroxy-3-nonyl)adenines (EHNA and THNA) have been determined. All isomers inhibited the replication of herpes simplex virus (HSV) and inhibited DNA synthesis in HSV-infected cells. The two enantiomers of EHNA, (+)-EHNA and (-)-EHNA, displayed equal antiviral activities. This is in contrast to their activities as inhibitors of adenosine deaminase (ADA); (+)-EHNA is a 250-fold more potent inhibitor of ADA than (-)-EHNA [Bessodes et al. Biochem. Pharmac. 31, 879 (1982)]. The antiherpes activity of (+)-THNA was only slightly less than that of the EHNA isomers, whereas (-)-THNA was somewhat less active. The abilities of the four isomeres of EHNA and THNA to inhibit DNA synthesis in HSV-infected cells correlated with their abilities to inhibit virus multiplication. EHNA failed to inhibit HSV DNA polymerase activity in extracts from infected cells. Moreover, addition of EHNA to infected cells at 6 hr post-infection resulted in no inhibition of DNA synthesis. These results are inconsistent with a direct inhibition of macromolecular DNA synthesis by EHNA. Treatment of HSV-infected cells with EHNA produced a 2- to 4-fold decrease in levels of the four DNA precursors, deoxyribonucleoside 5'-triphosphates (dNTPs). This treatment had much less effect on dNTP levels in uninfected cells.
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PMID:Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells. 631 87

The effects of degradative enzymes and enzyme inhibitors were examined on the inhibitory actions of adenosine, AMP and ATP on atrial muscle and on the cholinergic responses of the ileum to transmural stimulation of the guinea-pig, in order to determine whether ATP responses are mediated by its breakdown products, AMP and adenosine. In both the atria and the ileum, adenosine deaminase reduced responses to ATP, although when combined with 5'-nucleotidase it had no further effect. In the atrium, the 5'-nucleotidase inhibitor, alpha,beta-methylene ADP (APCP), had no effect on its own, but prevented the potentiating effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) on responses to ATP. In the ileum, EHNA had no effect, but APCP potentiated responses to ATP. The enzyme 5'-AMP deaminase was shown to have a non-specific inhibitory effect on purine responses in both preparations. It is concluded for both preparations, that (1) the inhibitory responses to ATP are partly mediated by AMP and adenosine following the ectoenzymatic breakdown of ATP, and partly mediated by ATP itself, and (2) that AMP as well as adenosine can act directly on P1-purinoceptors. It is suggested that of the two breakdown products of ATP, AMP and adenosine, a larger proportion of the response is mediated by AMP in the ileum, whereas adenosine is the major mediator in the atrium.
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PMID:Stimulation of P1-purinoceptors by ATP depends partly on its conversion to AMP and adenosine and partly on direct action. 632 Dec 10

The inhibition of herpes simplex virus (HSV) replication by 2'-deoxyadenosine (dAdo) is greatly potentiated by the presence of the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). HSV replication is inhibited by dAdo [in the presence of EHNA] or by 2'-deoxyguanosine (dGuo) at concentrations slightly lower than are necessary to inhibit growth of uninfected HeLa cells. Under conditions where virus replication is inhibited by greater than 99% with dAdo and EHNA, the level of dATP increases 50-fold or more, and synthesis of HSV DNA is inhibited. However, there is no depletion of any other DNA precursor, and HSV multiplication is not restored by simultaneous provision of dGuo, deoxythymidine, deoxycytidine, or a combination of all three of these nucleosides. Thus, the inhibition of HSV replication by dAdo cannot be explained as a block of precursor provision through inhibition of ribonucleotide reductase. In contrast, dGuo treatment of HSV-infected cells leads to depletion of dCTP, and virus multiplication is partially restored by provision of deoxycytidine. HSV-infected cells may serve as a useful system for study of the toxic effects of dAdo that are unrelated to inhibition of ribonucleotide reductase by dATP.
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PMID:Inhibition of herpes simplex virus replication by purine deoxyribonucleosides. 632 76

From human CCRF-CEM T-cells growing in continuous culture, we have selected, isolated, and characterized a clonal cell line, APHID-D2, with altered ribonucleotide reductase activity. In comparative growth rate experiments, the APHID-D2 cell line is less sensitive than the parental cell line to growth inhibition by deoxyadenosine in the presence of 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of adenosine deaminase. The APHID-D2 cell line has elevated levels of all four dNTPs. The resistance of the APHID-D2 cell line to growth inhibition by deoxyadenosine and the abnormal dNTP levels can be explained by the fact that the APHID-D2 ribonucleotide reductase, unlike the parental ribonucleotide reductase, is not normally sensitive to inhibition by dATP. These results suggest that the allosteric site of ribonucleotide reductase which binds both dATP and ATP is altered in the APHID-D2 line. The isolation of a mutant clone of human T-cells which contains a ribonucleotide reductase that has lost its normal sensitivity to dATP and which is resistant to deoxyadenosine-mediated growth inhibition suggests that a primary pathogenic target of accumulated dATP in lymphocytes from patients with adenosine deaminase deficiency may be the cellular ribonucleotide reductase.
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PMID:Characterization of a cultured human T-cell line with genetically altered ribonucleotide reductase activity. Model for immunodeficiency. 633 93

Human malaria infected erythrocytes show a dramatic increase in adenosine deaminase activity in vitro. Using recently developed culture techniques, adenosine deaminase-deficient human erythrocytes were infected in vitro with the major human pathogen Plasmodium falciparum. Adenosine deaminase activity was undetectable in the uninfected host red cells, but increased by 2-fold over normal levels in these cells with an 8% parasitemia. The enzyme in these cells appeared unique in that its activity was markedly elevated over that of other parasite purine enzymes, was not cross-reactive with antibody against human erythrocyte adenosine deaminase, and though inhibited competitively by deoxycoformycin was relatively insensitive to erythro-9-(2-hydroxy-3-nonyl) adenine. The use of adenosine deaminase-deficient erythrocytes for the in vitro cultivation of Plasmodium provides a unique system for the study of parasite enzyme and allows further insight into the purine metabolism of the intraerythrocytic malaria parasite.
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PMID:Human malaria parasite adenosine deaminase. Characterization in host enzyme-deficient erythrocyte culture. 636 11

Adenosine metabolism in C57BL/6 mouse spleen cells was studied. Adenosine triphosphate (ATP) levels in resting T cells were 26.9 +/- 3.4 ng/10(5) cells compared with 16.5 +/- 3.1 ng/10(5) cells in resting B cells. Cyclosporine (CSA) caused a prompt and severe ATP depletion in both T and B cells, which could be mitigated by the addition of adenosine. B cell ATP levels were returned to normal while T cell levels were only partially restored. The adenosine deaminase inhibitor erythro-9-(2 hydroxy-3 nonyl) adenine (EHNA) also caused ATP depletion in T and B cells, which could similarly be prevented in part by the addition of adenosine. However, when CSA and EHNA were combined, adenosine could no longer protect ATP pools and severe ATP depletion in T and B cells occurred. This suggests that CSA and EHNA affect different steps in the conversion of adenosine to ATP. Although both T and B cell ATP levels were affected by CSA, the ability of supplementary substrate to restore ATP levels to normal in B cells but not in T cells may explain the apparent selective effect of CSA impairing T cell functions with sparing of B cell functions. Furthermore, if causing ATP depletion is associated with immunosuppressive activity, EHNA may be useful in potentiating the immunosuppressive effects of CSA.
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PMID:Cyclosporine-induced adenosine triphosphate depletion in murine T and B lymphocytes. 637 58

Parenteral administration of the adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) results in a profound decrease in spontaneous motor activity in mice and rats. The inhibition of cortical ADA activity measured ex vivo parallels the decrease in spontaneous motor activity in a time-dependent manner. Nonetheless, a marked reduction in electroencephalographically defined sleep was observed in rats during a period when both spontaneous motor activity and ADA activity were profoundly inhibited. These data suggest that EHNA produces in rats a state of 'quiescent waking', which may be related to the observed inhibition of brain ADA activity.
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PMID:Sedative and electroencephalographic actions of erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA): relationship to inhibition of brain adenosine deaminase. 640 20


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