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)

2'-deoxyNAD was examined as a substrate for both mono(ADP-ribosyl)ation and poly(ADP-ribosyl)ation reactions. 2'-deoxyNAD is a substrate for the diphtheria toxin-catalyzed mono(ADP-ribosyl)ation of elongation factor-2, inactivating its function to enhance protein synthesis. On the other hand, 2'-deoxyNAD is a poor substrate for poly(ADP-ribose) polymerase. 2'-deoxyNAD was not synthesized intracellularly from deoxyATP, even when deoxyATP content was markedly increased by incubation of cells with deoxyadenosine and an adenosine deaminase inhibitor. 2'-deoxyNAD, because of its specificity, could be a quite useful reagent for the investigation of cellular mono(ADP-ribosyl)ation reactions.
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PMID:Utilization of 2'-deoxynad for ADP-ribose transfer reactions. 251 87

Previous work has shown that platelet-derived adenine nucleotides modulate neutrophil superoxide anion (O2-) generation. Additional studies were undertaken to characterize the effects of authentic adenosine (ADO) and its nucleotide derivatives on the inflammatory functions of human neutrophils. Stimulus-specific inhibition of neutrophil O2- generation by ADO in response to FMLP was verified. In addition, the ability of ATP, ADP, and AMP to limit neutrophil O2- generation induced by FMLP (0.2 to 0.5 microM) was demonstrated. The concentration producing 50% inhibition for nucleotide inhibition of neutrophil O2- generation was in the rank order of ADO (0.1 microM) less than AMP (0.5 microM) less than ADP less than or equal to ATP (5 microM). Guanine and inosine nucleotides (0.01 to 100 microM) did not inhibit FMLP-stimulated neutrophil O2- generation. Neutrophil degranulation in response to FMLP was only modestly inhibited by adenine nucleotides and ADO. Adenosine and ADP failed to affect chemotaxis of neutrophils stimulated with FMLP. The inability of non-metabolizable analogs to mimic the inhibitory effects of authentic ATP or ADP on the neutrophil O2- response suggested that metabolism of added nucleotides is necessary for their effectiveness. Both TLC and HPLC confirmed that ATP and ADP were converted to AMP and ADO after their incubation with unstimulated or FMLP-activated neutrophils. The addition of adenosine deaminase to neutrophil reaction mixtures in which conversion of added nucleotides was apparent removed detectable ADO but failed to completely abrogate the inhibition of neutrophil O2- generation by accumulated AMP. The kinetics of inhibition of FMLP-induced neutrophil O2- generation by ATP and ADP also indicated that conversion of these nucleotides to ADO and/or AMP may be essential for their ability to reduce neutrophil responses.
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PMID:Regulation of human neutrophil functions by adenine nucleotides. 253 67

A potential physiologic role of extracellular adenosine triphosphate (ATP) on platelet function is proposed in this report. It is widely accepted that ATP competitively inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Our observations of platelet aggregation with the agonists, collagen, epinephrine, and ADP in the presence of 180 mumol/L ATP could support this competitive nature of ATP. However, the disaggregation of maximally aggregated platelets induced by ATP, theophylline, or ATP plus theophylline indicates that additional mechanisms of ATP action may be present. Extracellular gamma-32P-ATP (7 pmol) labels surface-membrane proteins in intact platelets as demonstrated by several criteria. The reaction is Ca++-dependent. Stimulation by calcium occurs in the physiologic range of 1 to 5 mmol/L. Significant levels of phosphorylation occur within one minute with near maximal levels reached by five minutes. Platelet cyclic AMP (cAMP) levels were elevated in a dose-dependent fashion in cells incubated for four minutes with increasing amounts of extracellular ATP (18 to 540 nmol). The addition of ATP plus theophylline resulted in a synergistic stimulation of cAMP levels. ATP was not being hydrolyzed to adenosine by plasma nucleotidases, as demonstrated by the lack of effect of ten U of adenosine deaminase. The phosphorylation of surface proteins by extracellular ATP released from activated platelets may modulate platelet responsiveness to agonists at distances removed from the site of vascular injury. Phosphorylation may also play a role in signal transduction to regulate the levels of intracellular cAMP, which further inhibits platelet activation.
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PMID:Modulation of platelet function by extracellular adenosine triphosphate. 254 37

We compared the response of rat PC12 cells and a derivative PC18 cell line to the effects of adenosine receptor agonists, antagonists, and adenine nucleotide metabolizing enzymes. We found that theophylline (an adenosine receptor antagonist), adenosine deaminase, and AMP deaminase all decreased basal cyclic AMP content and tyrosine hydroxylase activity in the PC12 cells, but not in PC18 cells. Both cell lines responded to the addition of 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine, adenosine receptor agonists, by exhibiting an increase in tyrosine hydroxylase activity and cyclic AMP content. The latter finding indicates that both cell lines contained an adenosine receptor linked to adenylate cyclase. We found that the addition of dipyridamole, an inhibitor of adenosine uptake, produced an elevation of cyclic AMP and tyrosine hydroxylase activity in both cell lines. Deoxycoformycin, an inhibitor of adenosine deaminase, failed to alter the levels of cyclic AMP or tyrosine hydroxylase activity. This suggests that uptake was the primary inactivating mechanism of adenosine action in these cells. We conclude that both cell types generated adenine nucleotides which activate the adenosine receptor in an autocrine or paracrine fashion. We found that PC12 cells released ATP in a calcium-dependent process in response to activation of the nicotinic receptor. We also measured the rates of degradation of exogenous ATP, ADP, and AMP by PC12 cells. We found that the rates of metabolism of the former two were at least an order of magnitude greater than that of AMP. Any released ATP would be rapidly metabolized to AMP and then more slowly degraded to adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptor activation and the regulation of tyrosine hydroxylase activity in PC12 and PC18 cells. 257 81

Forskolin, a plant (Coleus forskohlii) diterpene, inhibits ADP-induced (human: IC50, 2.3 +/- 1.0 microM; rat: IC50, 1.2 +/- 0.5 microM) and collagen-induced (human: IC50, 2.4 +/- 1.2 microM; rat: 0.6 +/- 0.2 microM) platelet aggregation in human and rat platelet-rich plasma (PRP). Human blood levels of adenosine (Ado) are low (100-300 nM) as compared to levels in rat plasma (7.55 +/- 0.51 microM). Ado is a natural antiplatelet and vasodilatory agent produced by vascular endothelium, heart and other body tissues. If the plasma Ado is degraded by pretreatment of PRP with adenosine deaminase (ADA), forskolin inhibition on platelet aggregation is reduced by 2-4 fold both in human and rat blood. On the other hand, if the physiological steady state levels of Ado are maintained by collecting the blood in the presence of the inhibitors of ADA (2'-deoxycoformycin, dCF, 5 microM) and Ado uptake (dipyridamole, 10 microM or dilazep, 2 microM), forskolin inhibition (IC50, 3.2 microM) on platelet aggregation in human PRP is potentiated by 20-40 fold (IC50, 0.075-0.15 microM). Similar potentiated forskolin effect (IC50, 0.53 microM) is seen if the ADA-treated human PRP is replenished with a low level of Ado (50 nM) after ADA inactivation by dCF and Ado-uptake blockade by dilazep. If the plasma is replenished with a higher concentration of Ado (300 nM), greater potentiation is seen (IC50, 0.23 microM). Forskolin is 2-4 fold more inhibitory in rat PRP than in human PRP, partially due to the presence of higher levels of Ado in the rat plasma. These studies demonstrate an important role of plasma Ado in the antiplatelet activity of forskolin and this effect can be greatly potentiated by the clinically used drugs, dipyridamole and dilazep.
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PMID:Significance of plasma adenosine in the antiplatelet activity of forskolin: potentiation by dipyridamole and dilazep. 274 84

1. The effects of adenosine deaminase, inosine, alkylxanthines (8-phenyltheophylline (8-PT), theophylline and isobutylmethylxanthine (IBMX], dipyridamole, alpha, beta-methylene ADP (AOPCP) and ATP analogues (alpha, beta-methylene ATP and beta, gamma-methylene ATP) on evoked end-plate potentials (e.p.p.s) were investigated in innervated sartorius muscles of the frog, in which twitches had been prevented with tubocurarine. The effects of 8-PT and IBMX on the amplitude and quantal content of e.p.p.s were also investigated in innervated sartorius muscles of the frog, in which twitches had been prevented with high-magnesium solutions. 2. Adenosine deaminase reversibly increased the amplitude of e.p.p.s and prevented the reduction caused by exogenously applied adenosine on e.p.p. amplitude. The increase caused by adenosine deaminase was equivalent to the decrease caused by 12 +/- 5.8 microM-adenosine on e.p.p. amplitude. 3. Inosine, the product of adenosine deamination, was virtually devoid of effect on e.p.p.s. 4. The adenosine receptor antagonists at the frog neuromuscular junction, 8-PT and theophylline, increased in a concentration-dependent manner the amplitude of e.p.p.s in the presence of tubocurarine. 8-PT increased the amplitude and quantal content of e.p.p.s in the presence of high magnesium. IBMX, which does not behave as an adenosine receptor antagonist at the frog neuromuscular junction, decreased the amplitude of e.p.p.s in the presence of tubocurarine or high-magnesium solutions. 5. Dipyridamole, an adenosine uptake blocker, decreased the amplitude of e.p.p.s, and in a concentration that did not affect neuromuscular transmission potentiated the depressing effect of adenosine, but not that of 2-chloroadenosine, on the amplitude of e.p.p.s. 6. AOPCP, an inhibitor of 5'-nucleotidase, increased the amplitude of e.p.p.s and markedly attenuated the depressing effect of ATP, but not that of adenosine, on e.p.p. amplitude. 7. The ATP analogue, alpha, beta-methylene ATP, which is not a substrate for 5'-nucleotidase, was virtually devoid of effect on e.p.p.s. beta, gamma-Methylene ATP, which can be a substrate for 5'-nucleotidase, mimicked the depressing effect of ATP on e.p.p. amplitude, an effect which was also reduced by AOPCP. 8. It is concluded that in conditions in which the initial quantal content is assumed to be normal (1) endogenous adenosine depresses neuromuscular transmission, (2) at the neuromuscular junction adenosine is inactivated through a dipyridamole-sensitive uptake process, and (3) released adenine nucleotides might contribute to the pool of endogenous adenosine which modulates neuromuscular transmission.
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PMID:On the role, inactivation and origin of endogenous adenosine at the frog neuromuscular junction. 282 Dec 40

By means of agonist and enzyme experiments, the relative importance of endogenous adenosine, adenine nucleotides or other purines as modulators of cholinergic neuroeffector transmission in preparations of guinea-pig ileum muscle has been examined. Adenosine, 2-chloroadenosine, AMP, ADP, ATP and AMPPNP reversibly inhibited contractile responses to transmural stimulation of the guinea-pig ileum longitudinal muscle. 5'-adenylate deaminase dose-dependently antagonized the inhibitory effect of adenosine, AMP, ADP, ATP and AMPPNP, but not that of 2-chloroadenosine. 8-p-sulphophenyltheophylline, adenosine deaminase and 5'-adenylate deaminase enhanced contractile responses to transmural nerve stimulation. Adenosine deaminase and 5'-adenylate deaminase were virtually equiactive whereas 8-p-sulphophenyltheophylline was much more effective, and the theophylline derivative also enhanced contractile responses in preparations pretreated with adenosine deaminase or 5'-adenylate deaminase. Moreover, 8-p-sulphophenyltheophylline abolished the inhibition by dipyridamole, whereas adenosine deaminase and 5'-adenylate deaminase only partly antagonized the inhibitory effect of dipyridamole. Application of 5'-adenylate deaminase did not enhance the nerve-induced contractions in preparations pretreated with adenosine deaminase or a combination of dipyridamole and adenosine deaminase. In conclusion, adenosine deaminase and 5'-adenylate deaminase enhanced the nerve-induced contractions in the ileum, and, since 5'-adenylate deaminase was inactive after pretreatment with adenosine deaminase, this suggests that endogenous adenosine rather than 5'-adenine nucleotides modulated cholinergic neurotransmission in the ileum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:On the nature of endogenous purines modulating cholinergic neurotransmission in the guinea-pig ileum. 282 30

Incubation of hepatocytes from 24 h-starved rats in the presence of 0.5 mM-adenosine decreased gluconeogenesis from lactate, but not from alanine. The inhibition of gluconeogenesis was associated with a stimulation of ketone-body production and an inhibition of pyruvate oxidation. These metabolic changes were suppressed in the presence of iodotubercidin (an inhibitor of adenosine kinase), but were reinforced in the presence of deoxycoformycin (an inhibitor of adenosine deaminase); 2-chloroadenosine induced no change in gluconeogenesis from lactate. These data indicate that the inhibition of gluconeogenesis by adenosine probably results from its conversion into adenine nucleotides. In the presence of lactate or pyruvate, but not with alanine or asparagine, this conversion resulted in a decrease in the [ATP]/[ADP] ratio in both mitochondrial and cytosolic compartments. Adenosine decreased the Pi concentration with all gluconeogenic substrates.
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PMID:The mechanism by which adenosine decreases gluconeogenesis from lactate in isolated rat hepatocytes. 282 38

Supernates of thymic epithelial cell culture (STEC) strongly inhibit aggregation induced by addition of adenosine diphosphate (ADP: 1 microM) or thrombin (0.5 unit per ml) to washed platelet suspensions and accelerated the restoration from ADP-triggered aggregation. At the same time, STEC increased the level of platelet adenosine 3',5'-cyclic monophosphate (cyclic AMP) in a dose-dependent manner. Depending on the concentration used, thymosin fraction 5 increased the level of intracellular cyclic AMP ranging between 5 and 100 micrograms per ml, as well as inhibiting ADP-induced platelet aggregation. The activities of both STEC and thymosin fraction 5 were found to act exclusively on cyclic AMP phosphodiesterase activity in platelets. In contrast the supernates from Chang, HeLa, or HCC-M cells did not affect platelet aggregation induced by ADP, but slightly increased the cyclic AMP level (Chang, HeLa). Within 2 min after the treatment with STEC, more than 50% of the maximum inhibitory activity on platelet aggregation and increases in intracellular cyclic AMP were observed. These activities disappeared following STEC treatment with pronase E. STEC activity was found predominantly in the 1,000-50,000-dalton fractions. These activities were not altered when STEC was treated by adenosine deaminase. The level of prostaglandin E (PGE) derivatives in STEC was about two times that found in the control culture medium. These data suggest that the biological activity of STEC in the platelets might be attributed to thymosinlike polypeptides and PGE1.
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PMID:In vitro effect of a thymic epithelial culture supernate or thymosin fraction 5 on rabbit platelet aggregation and intracellular cyclic AMP levels. 282 98

A simple and fast ion pair reversed-phase high-performance liquid chromatographic method has been developed for the simultaneous determination of ATP, ADP, AMP, GTP, GDP, IMP, NADP+, NADPH+, NAD+, NADH, ADP-ribose, inosine, adenosine, hypoxanthine, and xanthine. This method allows us to have a complete picture of the most important nucleotides present in fresh human erythrocytes. Furthermore it is particularly useful in the study of the erythrocyte adenine nucleotide catabolism allowing the detection of degradation products such as IMP, inosine, adenosine, hypoxanthine, and xanthine. The separation of the compounds under investigation is achieved in less than 15 min using a reversed-phase 3-micron Supelcosil LC-18 column and adding tetrabutylammonium, as ion-pair agent, to the buffers. The short time of analysis, the high reproducibility of the system, and the accurate evaluation of the compounds of interest make this method particularly suitable for routine analysis. Finally it is possible to use this assay as an alternative method of measuring activities of enzymes which catalyze reactions involving some of these compounds, as in the case of Na+-K+ ATPase, AMP deaminase, and adenosine deaminase.
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PMID:A very fast ion-pair reversed-phase HPLC method for the separation of the most significant nucleotides and their degradation products in human red blood cells. 282 56


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