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)

The endogenous level of cyclic AMP in incubated synaptosomes from cerebral cortex of guinea pigs was investigated after the addition of various agents to the incubation medium. It appeared that the synaptosomal suspension already contained exogenous adenosine. Preincubation with theophylline or with adenosine deaminase (ADase) decreased both the exogenous level of adenosine and the intrasynaptosomal level of cyclic AMP. The level of cyclic AMP was reincreased by the addition of adenosine agonists, especially 2-chloroadenosine. This increase was antagonized by deoxyadenosine and was not inhibited by dipyridamole. These results suggest that the adenosine derivatives in the synaptic cleft regulate the level of cyclic AMP in nerve terminals through adenosine receptor on the presynaptic membrane. ADP, ATP, dopamine, and histamine also stimulate the formation of cyclic AMP in the ADase-treated synaptosomes.
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PMID:Change of cycle AMP level in synaptosomes from cerebral cortex; increase by adenosine derivatives. 625 52

Loss of ATP accompanying accumulation of dATP has recently been reported to occur in the erythrocytes and lymphoblasts of patients with T lymphocytic leukemia during treatment with deoxycoformycin, an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) that causes the accumulation of deoxyadenosine. We have studied the mechanisms responsible for adenine ribonucleotide depletion in cultured human CEM T lymphoblastoid cells treated with deoxycoformycin and deoxyadenosine. Accumulation of dATP was accompanied by depletion of total soluble adenine ribonucleotides without change in the adenylate energy charge, by the route ATP --> AMP --> IMP --> inosine --> hypoxanthine; conversion of IMP to AMP and de novo purine synthesis were inhibited in these cells. ATP degradation did not occur in a mutant of CEM that was incapable of phosphorylating deoxyadenosine, or in a B cell line with very limited ability to accumulate dATP. We found that dATP and ATP were both able to stimulate markedly the deamination of AMP by lymphoblast AMP deaminase; dAMP was a poor substrate for this enzyme (K(m) = 2.4 mM, vs. 0.4 mM for AMP). Similarly, dATP as well as ATP caused marked activation of IMP dephosphorylation by a lymphoblast cytoplasmic nucleotidase. Inhibition of intracellular AMP deaminase with coformycin prevented degradation of adenine ribonucleotides without affecting dATP accumulation. We propose that ATP-dependent phosphorylation of deoxyadenosine generates ADP and AMP. Simultaneously, dATP accumulation stimulates deamination of AMP, but not dAMP, and the dephosphorylation of IMP to inosine. Coupling of AMP degradation to ATP utilization in deoxyadenosine phosphorylation maintains the adenylate energy charge despite net depletion of cellular ATP.
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PMID:Mechanism of deoxyadenosine-induced catabolism of adenine ribonucleotides in adenosine deaminase-inhibited human T lymphoblastoid cells. 628 40

The effect of adenosine and adenine nucleotides on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta was studied. Adenosine (10(-5)-3 x 10(-4)M) decreased the contractile response of pulmonary artery and aorta evoked by electrical-field stimulation. The decrease was reversible. No tachyphylaxis developed. Inhibition of either adenosine deaminase by deoxycoformycin (3.6 x 10(-6)M) or of adenosine transport by dilazep (3 x 10(-6)M) did not alter the inhibitory effect of adenosine on the neurogenic contractions in the pulmonary artery. However, deoxycoformycin plus dilazep markedly enhanced the inhibitory effect of adenosine. The calcium antagonists nifedipine (1.5 x 10(-8)M) and nimodipine (1.3 x 10(-8)M) had no effect on the adenosine-induced inhibition. This was also the case with theophylline (5 x 10(-5)M), atropine (10(-7)M), and the prostaglandin synthetase inhibitors indomethacin (5 x 10(-5)M and suprofen (3 x 10(-5)M). The contractile response of the pulmonary artery elicited by exogenous (-)-noradrenaline (NA; 10(-9)-3 x 10(-4)M) was essentially not altered by adenosine (10(-5)-3 x 10(-4)M). Adenosine (10(-4)M) did not alter the spontaneous 3H-outflow from rabbit aorta preloaded with 3H-(-)-noradrenaline (3H-NA). Adenosine (10(-5)-3 x 10(-4)M), ADP (10(-4)M), ATP (10(-5)M), and inosine (10(-4)M) diminished the overflow of tritium from pulmonary artery and aorta preloaded with 3H-NA. The spontaneous outflow of tritium from aorta preloaded with 3H-NA consisted of 3H-NA (17%), 3H-dihydroxyphenylglycol (3H-DOPEG; 30%), 3H-dihydroxymandelic acid (3H-DOMA, 4%), 3H-O-methylated and deaminated metabolites (3H-OMDA; 42%), and 3H-normethanephrine (3H-NMN; 2%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-DOPEG and 2H-NMN, decreased 3H-NA, and did not alter 3H-DOMA and 3H-OMDA. The stimulation-evoked overflow of tritium for aorta preloaded with 3H-NA consisted of 3H-NA (31%), 3H-DOPEG (18%), 3H-DOMA (2%), 3H-ONDA (46%), and 3H-NMN (3%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-NA and 3H-DOPEG, decreased 3H-OMDA and did not alter 3H-DOMA and 3H-NMN. Adeosine (10(-6)-10(-4)M) did not alter the accumulation of 3H-NA (10(-8)M) by aorta. It is concluded that adenosine inhibits vascular sympathetic neuroeffector transmission by diminishing the release of transmitter from the nerve terminals.
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PMID:Inhibition of adrenergic neuroeffector transmission in rabbit pulmonary artery and aorta by adenosine and adenine nucleotides. 628 68

The ribose-modified chromophoric and fluorescent analog of ATP 2',3'-O-(2,4,6-trinitrocyclohexadienylidene) adenosine 5'-triphosphate (TNP-ATP) has been synthesized previously (Hiratsuka, T., and Uchida, K. (1973) Biochim. Biophys. Acta 320, 635-647 and Hiratsuka, T. (1976) Biochim. Biophys. Acta 453, 293-297). In the present study, four TNP-derivatives of ATP, ADP, AMP and adenosine were synthesized and compared for several chemical, spectral and enzymatic properties. Their visible absorption and fluorescent properties were found to be quite similar. Visible absorption and fluorescence spectra of TNP-derivatives were sensitive to solvent polarity. TNP-adenosine and TNP-AMP showed considerable substrate activities with adenosine deaminase and alkaline phosphatase, respectively. TNP-ATP proved to be an excellent substitute for ATP in adenylate kinase and myosin ATPase systems. The results indicate that these analogs are useful as chromophoric and fluorescent probes for hydrophobic regions in adenine nucleoside and nucleotide requiring enzymes.
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PMID:Biological activities and spectroscopic properties of chromophoric and fluorescent analogs of adenine nucleoside and nucleotides, 2',3'-O-(2,4,6-trinitrocyclohexadienylidene) adenosine derivatives. 629 7

1. Tubule fragments were isolated from renal cortex of fed rats. 2. Gluconeogenesis from lactate was significantly increased by low concentrations of exogenous ATP, ADP, AMP adenylyl (beta, gamma-methylene)diphosphonate and, to a lesser extent, by ITP and inosine. GTP was slightly inhibitory. Hypoxanthine was ineffective. Exogenous adenosine deaminase slightly decreased gluconeogenesis and was additive in effect to GTP. Adenosine deaminase did not abolish the stimulatory effects of ATP or cyclic AMP. 3. 40 microM ATP also stimulated gluconeogenesis from pyruvate, malate, succinate, 2-oxoglutarate and glutamine, but had no effect when glycerol or fructose were used as substrates. 4. With lactate as substrate the effect of 40 microM ATP was additive to the maximal stimulations of gluconeogenesis seen with 1 microM noradrenalin or 0.1 microM angiotensin II, but was not additive to the stimulatory effect of 0.1 mM cyclic AMP. 5.40 microM ATP had no effect upon either the tubule content of cyclic AMP or upon 45Ca efflux from prelabelled tubules. 6. Addition of ouabain or removal of extracellular K+ diminished the stimulatory effects of ATP and cyclic AMP. 7. Extracellular ATP was rapidly metabolized by tubule fragments, with resulting accumulation of adenosine. Further metabolism resulting in formation of inosine, hypoxanthine, xanthine and uric acid was also observed. Cyclic AMP was metabolized less rapidly, with no accumulation of adenosine. 8. The effects of purinergic agents on gluconeogenesis are discussed.
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PMID:Stimulation of renal gluconeogenesis by exogenous adenine nucleotides. 629 8

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 spontaneous formation of arsenic mononucleotides has been detected in mixtures of arsenate and inosine or adenosine or its deoxy analogues. These compounds have been separated by high-performance liquid chromatography and identified by their behavior in the presence of myokinase and adenylate deaminase. The nucleoside 5'-arsenates are formed preferentially to the 2'- and 3'-arsenate analogues. All arsenic nucleotides detected showed similar kinetic and equilibrium constants of formation: about 8 X 10(-4) M-1 S-1 and 2 X 10(-3) M-1, respectively. These values are several orders of magnitude greater than those of their phosphoric analogues. The adenosine 5'-arsenate was able to substitute for 5'AMP in the reaction of myokinase and adenylate deaminase. The substitutions of the 2'- or 3'-hydrogen for hydroxyl groups in the ribose moiety of this compound slightly affected its suitability as substrate for myokinase but had drastic effect in the case of adenylate deaminase. The half-life of the arsenic nucleotides, at pH 7.0 and 25 degrees C, ranged from 30 to 45 min. The lability of these compounds is increased during catalysis with myokinase. Results on the reaction mechanism of myokinase with adenosine 5'-arsenate indicate that the mixed-anhydride analogue to ADP, adenosine 5'-(arsenate phosphate), is not detected either because it is not formed in the reaction with this enzyme or because it is rapidly hydrolyzed.
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PMID:Arsenic mononucleotides. Separation by high-performance liquid chromatography and identification with myokinase and adenylate deaminase. 632 59

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


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