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)

1. The breakdown of the adenine nucleotide pool provoked by the replacement of the O(2)/CO(2) gas phase by N(2)/CO(2) was studied in isolated rat hepatocytes with the purpose of defining the pathway of the catabolism of AMP in anoxic conditions. 2. Approx. 40% of the adenine nucleotide pool was lost after 40-60 min of anoxia. In hepatocytes from fed rats there was a slow disappearance of ATP. This is explained by the presence of glycogen stores, allowing the generation of ATP by anaerobic glycolysis. In hepatocytes from 24h-starved rats, ATP almost completely disappeared within 5 min, and was partly replaced by an accumulation of AMP. This indicates that another mechanism protects the adenine nucleotide pool in the starved state. In both conditions, the loss of adenine nucleotides was mainly accounted for by an accumulation of uric acid, owing to the oxygen-dependence of urate oxidase. 3. Incubation of the hepatocytes before the suppression of O(2) with coformycin at concentrations known to inhibit selectively adenosine deaminase did not result in an accumulation of adenosine and did not influence the formation of uric acid. This indicates that the degradation of AMP does not proceed by way of 5'-nucleotidase under these conditions. In the presence of coformycin at concentrations which are inhibitory to AMP deaminase, however, the formation of uric acid was nearly suppressed, demonstrating that the initial degradation of AMP was catalysed by the latter enzyme. 4. The accumulation of AMP in the starved state can be explained by the pronounced decrease in ATP, the major stimulator of AMP deaminase, and the enhanced increase in P(i), one of its physiological inhibitors. The modifications of these effectors can also explain the increased inhibition of the cytoplasmic 5'-nucleotidase, shown by the accumulation of IMP in the absence of coformycin, in hepatocytes from starved rats. 5. Reoxygenation of the hepatocytes after 20 min of anoxia induced a prompt regeneration of ATP, which reached concentrations equal to the pre-existing concentration of AMP. 6. No explanation was found for the accumulation of IMP observed after preincubation of the hepatocytes with 0.1mum-coformycin, since the activities of the IMP-metabolizing enzymes were not influenced by this inosine analogue.
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PMID:The pathway of adenine nucleotide catabolism and its control in isolated rat hepatocytes subjected to anoxia. 708 1

Adenosine and the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), separately and in combination, were added to the perfusate of isolated rat hearts which were then subjected to ischaemia or anoxia. The effect of these infusates on the vascular competence of the myocardium subjected to oxygen deprivation of from 15-90 min was compared to control hearts. Vascular competence at selected time intervals was assessed from the distribution of injected. 1% sodium fluorescein in the cut surface of the ventricles. A region of non-perfusion surrounding the left ventricular lumen and involving 25% of the ventricular myocardium developed within 15 min of anoxic perfusion, with little change thereafter. Adenosine had no significant effect on this. The no-reflow phenomenon following ischaemia had similar distribution, but developed more slowly and eventually involved twice as much of the myocardium (59% after 90 min). Surprisingly, pre-treatment with adenosine greatly increased (from 14-46%) the extent of no-reflow after 30 min of ischaemia. Pre-treatment with EHNA caused a slight reduction (59-43%) in its extent but only after 60 min. Thus the no-reflow phenomenon which developed in ischaemic myocardium is unlikely to be due to the reduced vasodilatory action of adenosine.
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PMID:The influence of adenosine on the no-reflow phenomenon in anoxic and ischaemic hearts. 709 21

The concentrations of adenosine and other metabolic factors are known to be altered in the effluent of hypoxic hearts, but the relative contribution of these factors in elevating coronary flow has not been clarified. Langendorff prepared guinea pig hearts were perfused at constant pressure and were made mildly hypoxic so that flow increased but oxygen consumption remained unchanged. When the effluent of these hearts was reoxygenated and pH corrected and directed to perfuse similarly prepared recipient (bioassay) hearts, flow remained unchanged in recipient hearts. However, when donor hearts were made severely hypoxic so that oxygen consumption decreased, and recipient hearts were perfused at constant flow, the PO2, pH corrected effluent produced a large vasodilation in recipient hearts. This response was greatly attenuated in the presence of excess adenosine deaminase but completely abolished by theophylline. Thus the apparent loss of adenine compounds into the effluent may account for vasodilation during severe hypoxia, but not during mild hypoxia, if effluent levels of these compounds truly reflect perivascular levels.
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PMID:Heart bioassay of effluent of isolated, perfused guinea pig hearts to examine the role of metabolites regulating coronary flow during hypoxia. 728 37

Ischemia and reperfusion have been shown to cause damage to the endothelium as well as to the cardiac myocyte. Although the vasodilator response has been shown to be impaired following ischemia and reperfusion, the effect of a short period of global ischemia on the contractile response of the coronary vasculature is not clear. In the present study, coronary vasoconstriction in response to U46619, PGF2 alpha, 5-HT, and KCl was found to be depressed for at least 15 min following 15 min of in vitro global ischemia in rats hearts. Vasodilator blockers or inactivators were used in an effort to restore this depressed coronary response. Indomethacin (5 microM) was used to block production of vasodilator prostaglandins, L-NAME (30 microM) to block production of nitric oxide (NO), and adenosine deaminase (2.4 units/ml of coronary flow) to inactivate adenosine. None of these agents restored the normal coronary constrictor response following ischemia. When superoxide dismutase and catalase (both 20 micrograms/ml of coronary flow) were infused for 5 min before and after ischemia, the coronary response recovered more than 100% of its preischemic value by 15 min of reperfusion, but still remained depressed at 5 min reperfusion. These data suggest that free radicals produced during ischemia and/or reperfusion may be at least partly responsible for this temporary "stunning" of the coronary vasculature. Since the impaired contractile response was still present at 5 min reperfusion when the buffer was supplemented with oxygen radical scavengers, another mechanism must also be involved in this "stunning" process.
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PMID:Effects of short term ischemia and reperfusion on coronary vascular reactivity and myocardial function. 747 69

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% (p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p = 0.03) and 32% (p = 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.
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PMID:Reduction in cerebral ischemic injury in the newborn rat by potentiation of endogenous adenosine. 749 51

In anesthetized, paralyzed, and ventilated rats, hypoxia or intracarotid cyanide excited the carotid chemoafferents, whereas intracarotid dopamine and tyramine inhibited the chemoafferent discharges. The inhibition was abolished by chlorpromazine without attenuating the hypoxic excitation. Comparably, the hypoxic excitation was not attenuated by the following: 1) inhibition of nitric oxide synthase with NG-nitro-L-arginine; 2) inhibition of heme oxygenase with zinc protoporphyrin IX; 3) antagonism of ATP receptors with reactive blue 2; 4) antagonism of cholinergic receptors with atropine or trimethaphan; 5) inactivation of adenosine with adenosine deaminase; and 6) blockade of glutamate receptors with kynurenate. Systemic administration of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N'N'-tetraacetic acid, in doses reversibly blocking sympathetic ganglionic transmission, was also without effect. Cyanide microinjection (0.05-0.5 nmol) into the petrosal but not nodose ganglion elicited a rapid dose-dependent elevation of arterial pressure. We conclude that excitation of the chemoreceptor afferents by hypoxia/cyanide cannot be attributed to release of these agents nor to others by Ca(2+)-dependent mechanisms. The results suggest that the afferent nerves themselves might function as oxygen detectors.
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PMID:Dopamine or transmitter release from rat carotid body may not be essential to hypoxic chemoreception. 752 4

In this study the relative importance of adenosine deaminase and adenosine kinase in regulating extracellular adenosine concentration was investigated in rat hippocampal slices labelled with [3H]-adenine. The release of [3H]-purines evoked by electrical stimulation or energy depletion (oxygen and glucose deprivation) was measured and, using high-performance liquid chromatography (HPLC), the proportion of [3H]-label in the form of [3H]-adenosine, [3H]-inosine and [3H]-hypoxanthine was determined. In addition, endogenous purine release was measured by HPLC with UV detection. 10 microM 5-iodotubericidin (5-IT), an inhibitor of adenosine kinase, significantly increased endogenous adenosine release and altered the pattern of [3H]-purine release by increasing the proportion released as [3H]-adenosine, under basal conditions and after electrical stimulation or energy depletion. 5 microM erythro-9-(2-hydroxy-3-nonyl) adenosine (EHNA), an inhibitor of adenosine deaminase, also increased endogenous adenosine release and altered the pattern of [3H]-purine release evoked by energy depletion by decreasing the proportion of [3H]-label released as [3H]-hypoxanthine and [3H]-inosine, whilst approximately doubling that of [3H]-adenosine. In contrast, adenosine release was not altered by EHNA under basal conditions or electrical stimulation. It is concluded that under conditions which provide adequate oxygen and glucose, adenosine kinase plays a much greater role than adenosine deaminase in regulating the extracellular concentration of adenosine. However, adenosine deaminase becomes important in regulating extracellular adenosine concentration when adenosine formation is increased by energy depletion.
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PMID:Involvement of adenosine deaminase and adenosine kinase in regulating extracellular adenosine concentration in rat hippocampal slices. 763 32

Formation of tetrahedral transition intermediates is a key step in many enzyme catalyzed reactions. Much of our understanding of these and other intermediates, at the atomic level, has come from crystallographic studies of very few enzymes with bound, synthetic, transition-state analogues. Here we present the structure of adenosine deaminase, a zinc-metalloenzyme critical in both purine metabolism and development of the lymphoid system, having performed a stereospecific hydroxide addition to the C6 of inosine. This addition causes the O6 oxygen of inosine to assume an orientation analogous to the position of the amino leaving group of the tetrahedral intermediate in the enzyme-catalyzed hydrolytic deamination of adenosine to inosine.
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PMID:Crystallographic observation of a trapped tetrahedral intermediate in a metalloenzyme. 763 72

The crystal structure of urease from Klebsiella aerogenes has been determined at 2.2 A resolution and refined to an R factor of 18.2 percent. The enzyme contains four structural domains: three with novel folds playing structural roles, and an (alpha beta)8 barrel domain, which contains the bi-nickel center. The two active site nickels are 3.5 A apart. One nickel ion is coordinated by three ligands (with low occupancy of a fourth ligand) and the second is coordinated by five ligands. A carbamylated lysine provides an oxygen ligand to each nickel, explaining why carbon dioxide is required for the activation of urease apoenzyme. The structure is compatible with a catalytic mechanism whereby urea ligates Ni-1 to complete its tetrahedral coordination and a hydroxide ligand of Ni-2 attacks the carbonyl carbon. A surprisingly high structural similarity between the urease catalytic domain and that of the zinc-dependent adenosine deaminase reveals a remarkable example of active site divergence.
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PMID:The crystal structure of urease from Klebsiella aerogenes. 775 94

The pH dependency of the binding of ligands to adenosine A2a receptors in rat striatal membranes was examined. For those agonists sensitive to adenosine deaminase a solubilised membrane preparation was used. A two- to fourfold increase in affinity was observed for CGS-21680, 5'-N-ethylcarboxamidoadenosine, adenosine, 3'-deoxyadenosine, 5'-deoxyadenosine, inosine, and N6-methoxypurine riboside on lowering the ambient pH from 7.0 to 5.5. In contrast, no such pH dependency was observed with 2'-deoxyadenosine, although 2'-methoxyadenosine binding was pH dependent. This effect on the affinity of CGS-21680 was reduced by diethylpyrocarbonate and restored by hydroxylamine and implied a pK value of 7.0 for the histidine residue involved. No such dependence was observed with cyclopentyltheophylline or dimethylpropargylxanthine. It is concluded that one of the histidines conserved in the adenosine receptor binding site acts as a hydrogen bond donor to the oxygen of the 2'-hydroxyl group of adenosine agonists.
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PMID:Role of histidine residues in the adenosine A2a receptor ligand binding site. 793


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