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:3.5.4.17 (adenosine deaminase)
5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Adipocytes isolated from rats 6--9 days after adrenalectomy had significantly increased sensitivity to insulin action against noradrenaline-stimulated lipolysis. In the presence of adenosine deaminase there was no significant difference in insulin sensitivity between cells from adrenalectomized and sham-operated rats. 2. Adipocytes from adrenalectomized rats had decreased lipolytic responses to all concentrations of noradrenaline and glucagon tested and a decreased lipolytic response to low but not high concentrations of corticotropin. There was no difference in lipolytic response to theophylline after adrenalectomy. Adenosine deaminase corrected the differences in response to noradrenaline and glucagon resulting from adrenalectomy. 3. In the presence of adenosine deaminase rates of lipolysis, after stimulation by high concentrations of noradrenaline, glucagon, corticotropin or theophylline, were the same in cells from adrenalectomized or sham-operated rats. 4. These findings and previously reported effects of adenosine and adrenalectomy on adipocyte function are discussed. It is proposed that changes in adipocyte hormone responsiveness after adrenalectomy may result from changes in adenosine metabolism or release.
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PMID:Alterations in response of rat white adipocytes to insulin, noradrenaline, corticotropin and glucagon after adrenalectomy. Correction of these changes by adenosine deaminase. 21 18

A cell culture system has been utilized to measure the effects of drugs on DNA synthesis in uninfected and HSV-(herpes simplex virus)-infected KB cells. DNA from HSV-infected cells was separated into viral and cellular components by isopycnic centrifugation in CsCl gradients. The amount of [3H]thymidine incorporated into acid-insoluble material was measured in the absence and presence of drugs. Dose-response relationships were established by linearly regressing the probit value of the percent inhibition DNA synthesis against the logarithm of drug concentration. Fifty percent inhibitory (I50) concentrations were interpolated from the corresponding regression lines for inhibition of the following: (i) DNA synthesis is uninfected KB cells, (ii) total DNA synthesis in HSV-infected KB cells (iii) cellular DNA synthesis in HSV-infected cells, and (iv) viral DNA synthesis in HSV-infected cells. We have derived an index (SI, selective index) that quantifies the preferential inhibition of viral or uninfected cellular DNA synthesis. This index can be expressed as SI = log10 I50 concentration for DNA synthesis in uninfected cells divided by I50 concentration for viral DNA synthesis in HSV-infected cells. The SI is positive if viral DNA synthesis is inhibited preferentially and negative if uninfected cellular DNA synthesis is more strongly inhibited. A positive SI value of 0.5 was obtained for the clinically useful antiviral drug arabinosyladenine (ara-A) and a value of 0.4 for its metabolite, arabinosylhypoxanthine (ara-H). Although the adenosine deaminase inhibitor coformycin greatly increased the potency of ara-A, the inhibitor did not increase the selectivity of the drug (SI = 0.3). Stallimycin (distimycin A) (SI = 0.3) and phosphonoacetic acid (SI = 0.3) were similarly effective in preferentially inhibiting the synthesis of HSV DNA. In contrast, arabinosylcytosine (ara-C) and ribavirin inhibited DNA synthesis in uninfected cells to a greater degree than viral DNA synthesis (SI = -0.5 and -1.9, respectively). An analysis of the advantages and limitations of this experimental procedure is made and the suggestion is offered that the in vitro determination of a drug's selective index may be a valid predictor of clinical usefulness.
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PMID:The selective inhibition of viral DNA synthesis by chemotherapeutic agents: an indicator of clinical usefulness? 21 84

A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine nucleoside from enzymatic deamination to the more weakly active metabolite, hypoxanthine arabinoside. Comparing the combination to vidarabine alone, a significant increase (10-fold) of the antiviral activity of the combined drugs was observed against herpes and vaccinia viruses in tissue culture and subcutaneously, against cranial herpesvirus infections in mice. Several other investigators have also recently reported several-fold enhancement of vidarabine activity by newly described deaminase inhibitors. They observed that plaque formation by several large DNA-containing viruses (herpes, vaccinia, varicella zoster) and an RNA-containing oncogenic virus was markedly prevented by the combination compared to vidarabine alone. In animals, enhanced protection (increased survivors) and/or highly significant increase in the life span of dying mice treated with the 2-drug combination, was also observed compared to vidarabine administered singly. These observations in animals clearly indicate that combination studies with vidarabine (Vira-ATM) and co-vidarabine (deaminase inhibitor) deserve serious consideration as future therapy for systemic virus infections in man including herpesvirus encephalitis.
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PMID:Effect of a novel adenosine deaminase inhibitor (co-vidarabine, co-V) upon the antiviral activity in vitro and in vivo of vidarabine (Vira-Atm) for DNA virus replication. 21 90

ACTH at levels as low as 0.05 mU/ml stimulated lipolysis, protein kinase and cyclic AMP accumulation in isolated fat cells from fed and fasted rats. Changes in cyclic AMP levels and in the protein kinase activity ratio were well correlated temporally. The protein kinase activity ratio was potentiated by adenosine deaminase. A sudden increase or decrease in either ACTH or dibutyryl cyclic AMP concentration was associated with a rapid and corresponding change in the rate of glycerol production. With ACTH, the changes in glycerol production were accompanied by appropriate changes in cyclic AMP levels. Actinomycin-D (10 UM) did not affect lipolysis or cyclic AMP accumulation activated by ACTH in fat cells.
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PMID:The correlation of cyclic AMP and protein kinase activity in adipocytes with lipolysis stimulated by ACTH: the effect of adenosine deaminase and actinomycin D. 21 72

1. The maximal activities of 5'-nucleotidase, adenosine kinase and adenosine deaminase together with the Km values for their respective substrates were measured in muscle, nervous tissue and liver from a large range of animals to provide information on the mechanism of control of adenosine concentration in the tissues. 2. Detailed evidence that the methods used were optimal for the extraction and assay of these enzymes has been deposited as Supplementary Publication SUP 50088 (16pages) at the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K.,from whom copies can be obtained on the terms indicated in Biochem. J. (1978), 169, 5. This evidence includes the effects of pH and temperature on the activities of the enzymes. 3. In many tissues, the activities of 5'-nucleotidase were considerably higher than the sum of the activities of adenosine kinase and deaminase, which suggests that the activity of the nucleotidase must be markedly inhibited in vivo so that adenosine does not accumulate. In the tissues in which comparison is possible, the Km of the nucleotidase is higher than the AMP content of the tissue, and since some of the latter may be bound within the cell, the low concentration of substrate may, in part, be responsible for a low activity in vivo. 4. In most tissues and animals investigated, the values of the Km of adenosine kinase for adenosine are between one and two orders of magnitude lower than those for the deaminase. It is suggested that 5'-nucleotidase and adenosine kinase are simultaneously active so that a substrate cycle between AMP and adenosine is produced: the difference in Km values between kinase and deaminase indicates that, via the cycle, small changes in activity of kinase or nucleotidase produce large changes in adenosine concentration. 5. The activities of adenosine kinase or deaminase from vertebrate muscles are inversely correlated with the activities of phosphorylase in these muscles. Since the magnitude of the latter activities are indicative of the anaerobic nature of muscles, this negative correlation supports the hypothesis that an important role of adenosine is the regulation of blood flow in the aerobic muscles.
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PMID:Activities and some properties of 5'-nucleotidase, adenosine kinase and adenosine deaminase in tissues from vertebrates and invertebrates in relation to the control of the concentration and the physiological role of adenosine. 21 26

The platelets of an infant with severe combined immune deficiency and adenosine deaminase deficiency showed markedly diminished responses to ADP-induced aggregation in vitro. This abnormality was corrected by the addition of purified adenosine deaminase in vitro. Exogenous adenosine added to platelet-rich plasma caused markedly prolonged inhibition of ADP-induced aggregation. This was shown by isotopic studies to be due to slow clearance of adenosine and hence persistence of this nucleoside. Direct assay for adenosine deaminiase in plasma and platelet lysates of the patient confirmed the very low activity of this enzyme. Raised cAMP levels were demonstrated in his platelets. The deranged adenosine metabolism and raised cAMP in the platelets of this child with severe combined immunodeficiency may explain the altered response to ADP. Despite the in vitro platelet aggregation abnormality, the patient had no clinical evidence of impaired hemostasis.
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PMID:In vitro platelet abnormality in adenosine deaminase deficiency and severe combined immunodeficiency. 21 40

Inhibition of rat skeletal muscle adenylate deaminase by creatine phosphate reported previously is due to inorganic pyrophosphate present as a contaminant in commercial preparations of creatine phosphate. This conclusion is based on the following evidence: a compound that inhibits adenylate deaminase can be separated from commercially prepared creatine phosphate by ion exchange chromatography; the inhibition by "creatine phosphate" and by the separated inhibitory compound is relieved by treatment with inorganic pyrophosphatase; inhibition by inorganic pyrophosphate is similar to that produced by unpurified creatine phosphate; and pyrophosphate is present in commercially available creatine phosphate in amounts sufficient to account for the inhibition. Some commercial preparations of creatine phosphate contain much less pyrophosphate than others; these preparations are only weakly inhibitory. Inorganic triphosphate is a more powerful inhibitor of the enzyme than pyrophosphate; it may also be present as a contaminant in creatine phosphate.
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PMID:Creatine phosphate inhibition of adenylate deaminase is mainly due to pyrophosphate. 21 95

Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; erythro-9-[3-(hydroxynonyl)]adenine), a reversible inhibitor of adenosine deaminase, significantly inhibits replication of herpes simplex virus (HSV), whereas the more active inhibitor of the deaminase, 2'-deoxycoformycin, does not. At 10 micron EHNA, which does not affect viability, growth, or DNA synthesis of uninfected HeLa cells, production of HSV and HSV-specific DNA is inhibited 75-90% and 60%, respectively. HSV multiplies normally in cells pretreated with EHNA and washed to remove this inhibitor. EHNA (10 micron) also markedly potentiates the toxicity of adenine arabinonucleoside and of cordycepin (3'-deoxyadenosine) against HeLa cells and against the production of HSV in those cells. Cordycepin alone (10 micron) does not inhibit HSV replication whereas in combination with 10 micron EHNA there is a greater than 99% inhibition of virus production. Under these conditions, RNA synthesis is inhibited by more than 80% whereas protein and DNA synthesis are inhibited to a lesser extent; in this system, virtually all of the DNA synthesis in infected cells is that of host DNA. Thus, EHNA appears to affect the synthesis of HSV DNA specifically in two different ways, depending on whether it is used alone or in the presence of cordycepin.
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PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine as a specific inhibitor of herpes simplex virus replication in the presence and absence of adenosine analogues. 21 93

A number of 2',3'- and 3',5'-di-O-acyl derivatives of 9-beta-D-arabinofuranosyladenine (1) were prepared and evaluated as antivirals. These compounds, designed as prodrugs of 1, offer a range of solubilities and lipophilicities, as well as a resistance to adenosine deaminase, that render some as being attractive as possibly useful antiviral agents. Of particular note is 9-(2,3-di-O-acetyl-beta-D-arabinofuranosyl)adenine that was found to be effective as a topical agent in a guinea pig model of genital herpes.
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PMID:Prodrugs of 9-(beta-D-arabinofuranosyl)adenine 2. Synthesis and evaluation of a number of 2',3'- and 3',5'-di-O-acyl derivatives. 21 13

The minimum inhibitory concentration (MIC) of adenine arabinoside (ara-A) in rabbit kidney microtiter tissue cultures (RK-13) to a prototype strain of herpes simplex virus, type 1 (E115) based upon inhibition of cytopathic effects is 1.5 mug/ml. In this system, the MIC of arabinosylhypoxanthine (ara-Hx), the major in vivo metabolic derivative of ara-A, is 75 mug/ml. Inhibition of cytopathic effects of herpes simplex virus, type 1 (HSV-1) in microtiter wells of RK-13 cells varies directly with the concentrations of ara-A or ara-Hx, and inversely with residual HSV-1. The MIC of ara-A for HSV-1 in RK-13 cells is 5-20 times lower than similar measures with vero renal, mouse embryo, or human foreskin cultures. With RK-13 tissue cultures in microtiter plates, an assay for "ara-A equivalents" in human body fluids was developed which compares in sensitivity with high pressure liquid chromatography and has the advantage of simultaneously measuring combined antiherpesvirus effects of ara-A and its major metabolic derivative, ara-Hx. In vitro checkerboard studies in RK-13 cells confirmed that ara-A and ara-Hx in combination had antiviral effects which are synergistic. The total of the fractional MIC of ara-A plus ara-Hx in combination also varies inversely with residual HSV-1 in microtiter wells. Because virus adsorption is complete at 2 h before specimens to be tested are added in this assay, and because human interferon is not measured in rabbit cells, the antiviral assay is not affected by the presence of type-specific antiherpesvirus antibody or human interferon.Antiviral activity (AVA) was assayed as ara-A equivalents in sera and urines from 10 patients with serious herpesvirus infections who received 2.5-20 mg/kg daily of ara-A by intramuscular or intravenous routes. When a dosage schedule of 10 mg/kg per day or more was used, sustained concentrations of AVA that ranged from 0.8 to 14.4 mug/ml were found. When an inhibitor of adenosine deaminase (covidarabine) was not added to the specimens, mean serum concentrations were congruent with3.0 mug/ml (10 mg/kg per day, i.v.), and 4.1 mug/ml (20 mg/kg per day). However, in a single patient given 20 mg/kg of ara-A daily with covidarabine immediately added to the sera, the mean concentration of AVA was 12.9 mug/ml. Urines contained even higher AVA. Assays of 19 sera were performed both by microbiologic assay for AVA and by high pressure liquid chromatography for ara-A and ara-Hx. AVA was greater by microbiologic assay, and was greater than that which could be accounted for by stoichiometric chromatographic measures of ara-A and ara-Hx. These results with sera of treated patients are consistent both with the in vitro synergy of ara-A and ara-Hx found by checkerboard titrations, and with the beneficial responses to ara-A of patients with herpesvirus infections reported here and elsewhere.
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PMID:Antiherpesvirus activity in human sera and urines after administration of adenine arabinoside: in vitro and in vivo synergy of adenine arabinoside and arabinosylhypoxanthine in combination. 21 24


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