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 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

Adenine nucleotide levels were measured in extracts of murine calvaria after different periods of culture with or without parathyroid hormone (PTH; 10(-8) M) or PGE2 (10(-7) M). In control calvaria the energy charge, (ATP + 1/2 ADP)/(ATP + ADP + AMP), remained at close to 0.7 over a 24 hour culture period. However, bones cultured with PTH or PGE2 showed a transient fall in the energy charge down to 0.5. This was not associated with a fall in total adenine nucleotides. The rate of adenosine metabolism in cultured bone in vitro was studied by determining the contents of adenosine, inosine, 2-deoxyadenosine, 2-deoxyinosine and hypoxanthine in the culture medium. There was a continuous increase in adenosine, inosine and hypoxanthine as well as a disappearance of medium 2-deoxyadenosine that was accounted for by appearance of 2-deoxyinosine. The deaminating activity could only partly be accounted for by activity in the medium and thus probably mainly resides in the bone cells. PTH (10(-8) M) did not alter the rate of disappearance of 2-deoxyadenosine or adenosine deaminase activity determined in bone extracts. The results demonstrate that two substances that increase calcium mobilization from bone alter ATP utilization and/or synthesis without significantly influencing adenosine production or metabolism.
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PMID:Adenine nucleotide levels and adenosine metabolism in cultured calvarial bone. 633 38

The hypothesis was investigated that myocardial hypoxia stimulates the production of platelet anti-aggregatory substances in the heart. Rabbit hearts were perfused under normoxic or hypoxic conditions and the coronary and interstitial effluents from the hearts were separated. The occurrence of anti-aggregatory activity (AAA) in the interstitial effluent was detected in vitro from its capacity to inhibit ADP-induced platelet aggregation. The AAA in the effluent was deemed to be prostacyclin (PGI2) if its release was abolished by administration of indomethacin (5 X 10(-5) M) to the heart, and to be adenosine if it was abolished by incubation of the effluent with adenosine deaminase. During normoxic perfusion, only a minor efflux of AAA appeared from the heart; neither was the efflux appreciable during mild hypoxia (30 or 60% O2). Severe hypoxia (venous pO2 below 5 kPa), on the other hand, was associated with a marked release of AAA. Incubation of hypoxic effluent with adenosine deaminase resulted in a small loss of activity, indicating that the major part of the AAA was not ascribable to adenosine. After indomethacin treatment, significant amounts of AAA still appeared in the effluent during hypoxia. However, unlike the case before indomethacin, this AAA was completely destroyed by adenosine deaminase. From these data, we conclude that myocardial hypoxia can mobilize either of two independent mechanisms for protection against platelet aggregation: an activation of the synthesis and release of prostacyclin, and a more complete breakdown of ATP, leading to an increased formation and efflux of adenosine.
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PMID:Hypoxia elicits liberation of anti-aggregatory substances from isolated rabbit hearts. 635 93

Low ATP/ADP ratios have been reported consistently for nucleotide levels of mononuclear cells separated from peripheral blood by conventional techniques. We have established that these low values (mean 2.3:1) were not due to cell damage or poor viability, but resulted from heavy platelet contamination, which is unavoidable when heparinized blood is used. The results reflect the low ATP/ADP ratios (mean 1.6:1) characteristic of platelets. Platelet-free extracts from defibrinated blood had very high ATP/ADP ratios (mean 17.4:1). The initial finding of detectable amounts of deoxy-ATP and deoxy-GTP in mononuclear cells from children with two distinct inherited immunodeficiency disorders [adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency respectively] many have been due to contamination by nucleated erythrocytes as well as platelets in non-defibrinated preparations. Defibrination before nucleotide extraction of mononuclear cells from a patient with T-cell leukaemic/lymphoma treated with the ADA inhibitor deoxycoformycin enabled the demonstration of grossly raised deoxy-ATP levels relative to deoxy-ADP levels (ratio 16.1:1), associated with severe ATP depletion. This reciprocal relationship between ATP and dATP was found by us previously in the erythrocytes in inherited ADA deficiency. These findings underline the importance of extracts uncontaminated by platelets, or nucleated erythrocytes, in the evaluation of lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes.
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PMID:Importance of platelet-free preparations for evaluating lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes. 641 55

The primary goal of this study was to determine whether the slowing of atrioventricular (AV) conduction by ATP is caused by ATP per se or is mediated by adenosine formed from ATP degradation. We assessed the effects of ATP, beta, gamma-methylene ATP, ADP, AMP, and adenosine on AV conduction time in the isolated perfused guinea pig heart. The cardiac effluent was collected and analyzed for its content of adenine nucleotides and nucleosides. Perfused ATP was rapidly and almost completely broken down to AMP and adenosine; only 2.5 +/- 0.5% of the infused ATP was recoverable in the effluent. A significant correlation was found between the effluent concentration of adenosine and atria-to-His bundle (A-H) conduction time. Compounds that altered the effect of adenosine on A-H conduction likewise altered the effect of ATP: (1) aminophylline, a competitive antagonist of adenosine, antagonized the ATP-induced A-H prolongation; (2) adenosine deaminase, the enzyme responsible for the deamination of adenosine to inosine, reduced the effect of ATP by 82%; (3) the adenosine transport blockers NBMPR and dipyridamole markedly enhanced the effect of ATP; and (4) EHNA, an inhibitor of adenosine deaminase, potentiated the effect of ATP. Furthermore, the less hydrolyzable ATP analog, beta, gamma-methylene ATP, was less potent than ATP in causing A-H prolongation. We conclude that the adenosine-like action of ATP on the guinea pig AV node requires that ATP first be degraded to adenosine.
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PMID:Effects of adenosine and adenine nucleotides on the atrioventricular node of isolated guinea pig hearts. 649 45

Administered intracisternally, adenosine (ADO), 2-chloroadenosine (CADO), adenosine-5'-cyclopropylcarboxamide (ACC) and adenosine-5'-ethylcarboxamide (AEC) caused dose-related increases in hot plate reaction times in mice. The rank order of potency was AEC=ACC greater than CADO greater than ADO and ACC exerted demonstrable effects with doses as low as 10 ng/mouse. ADO itself was more potent than AMP, ADP, ATP and several other related compounds of interest. Theophylline, caffeine and 8-phenyltheophylline antagonized the antinocisponsive effect of CADO or ACC. Papaverine (an adenosine uptake blocker) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA: an adenosine deaminase inhibitor) potentiated the effect of ADO. EHNA did not potentiate the action of CADO in this procedure. The antinocisponsive effect of CADO was not antagonized by a host of neurally active agents including naloxone, clonidine and RO 20-1724. Time course studies indicated that the antinocisponsive effect of ADO was transient with the peak effect occurring 5 min after injection and disappearing by 60 min, whereas the effect of CADO persisted for at least 90 min. Intracisternally administered CADO also caused a pronounced hypothermia, loss of muscle tone and was active in the mouse writhing test. Taken together, these data demonstrate that purine exert potent in vivo behavioral effects and are consonant with the existence of a central purinergic P1-receptor which is amenable to selective pharmacological manipulation.
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PMID:In vivo behavioral assessment of central nervous system purinergic receptors. 689 75

dATP, dADP, and dAMP equalled or exceeded the depleted levels of ATP, ADP, and AMP in erythrocytes from two children with adenosine deaminase (ADA; EC 3.5.4.4) deficiency. dATP and dADP were identified in the mononuclear cells of only one child. The levels of deoxyadenosine compounds fell dramatically after enzyme replacement therapy and were no longer detectable in the urine or in mononuclear cells. Erythrocyte adenosine nucleotide levels showed a corresponding increase. Intact erythrocytes prior to treatment contained adenine, presumed to be from deoxyadenosine degraded during extraction. Adenosine at high concentrations in vitro increased both dATP and ATP levels and decreased intracellular deoxyadenosine levels. There was no significant deamination of either [8-14C]adenosine or deoxyadenosine by intact ADA-deficient erythrocytes. About 90% of adenosine was metabolized to ATP at substrate concentrations from 10-100 microM, compared to 40-60% of deoxyadenosine metabolized to dATP. These studies suggest that (i) high intracellular deoxyadenosine levels may be necessary in vivo to sustain the raised dATP levels in ADA deficiency. (ii) When ADA is inhibited or absent, deoxyadenosine is removed rapidly from the circulation by the human erythrocyte utilizing an adenosine transport system linked to both ADA and adenosine kinase (EC 2.7.1.20).
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PMID:Formation and degradation of deoxyadenosine nucleotides in inherited adenosine deaminase deficiency. 698 23

Studies on the action of adenine nucleotides on the Con A-induced blast transformation of rat thymocytes have shown that addition of milimolar concentrations of AMP and ADP to the cultural medium as well as that of adenosine produce an inhibitory effect on the reaction. Addition to the cells of adenosine deaminase almost completely abolishes this effect. Unlike the nucleotides, the suppressant effect of ATP on thymocyte proliferation is less pronounced and is not reversed by addition of adenosine deaminase. cAMP and ATP given in the concentrations sufficient for giving rise to the protein kinase reaction and ammonium ions (1 mM) have no effect on thymocyte blast transformation. The latter is appreciably suppressed by 1 mM pyrophosphate and almost completely by papaverine and curantyl. The nucleotides added to the thymocytes get dephosphorylated, however, extracellular adenosine is not accumulated during 80 minutes, its concentration being of the order of 10(-6) M.
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PMID:[Effect of adenosine and adenine nucleotides on rat thymocyte blast transformation induced by concanavalin A]. 698 79

Hot water extracts of Mo-er (1 gm by 15 ml of water), an oriental food (Auricularia auricula), inhibit strongly both human and rat platelet ADP-induced aggregation. HPLC analysis of two varieties of Mo-er, A. auricula and A. polytricha (a black tree fungus), shows that they contain adenosine (Ado), 133 and 154 micrograms per gram of dry fungus, respectively. The inhibition of ADP-induced platelet aggregation by Mo-er extracts and by Ado was compared. Mo-er extracts caused a more rapid onset and a longer duration of inhibition that produced by equivalent amounts of Ado. Furthermore, Mo-er extract treated with adenosine deaminase to degrade the Ado retained the capacity to inhibit platelet aggregation. The inhibitory effects of Mo-er extracts of ADP-induced human platelet aggregation are greatly potentiated by the inhibitors of cyclic AMP phosphodiesterase such as oxagrelate (phthalazinol) and papaverine. The inhibition of platelet aggregation is only partially blocked by 2',5'-dideoxy-adenosine (DDA), an inhibitor of platelet adenylate cyclase and 5'-deoxy, 5'-methylthioadenosine (MTA), an antagonist of ADO receptors. ADP-induced rat platelet aggregation is strongly inhibited by Mo-er extracts, but not by Ado. This inhibition is not reversed by either DDA or MTA. These findings indicate that Mo-er extracts contain an agent (or agents) in addition to Ado, that blocks platelet aggregation by a mechanism that does not involve the platelet cyclic AMP system.
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PMID:Inhibition of human and rat platelet aggregation by extracts of Mo-er (Auricularia auricula). 698 40

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


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