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)

There is evidence that phosphatidylcholine secretion in type II pneumocytes is stimulated by adenosine and adenine nucleotides and that the effect of adenosine is mediated by the A2 subtype of the P1 purinoceptor. To determine if the effect of ATP is also mediated by the same receptor following its catabolism to adenosine or by the P2 purinoceptor we compared the effects of adenosine and ATP. Adenosine and terbutaline stimulated phosphatidylcholine secretion approx. 2-fold, while ATP stimulated it by more than 3-fold, essentially to the same extent as the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate. The stimulatory effect of adenosine but not of ATP was abolished by adenosine deaminase. The effect of ATP was markedly diminished by the P2 desensitizing agent alpha,beta-methylene ATP, but only slightly by the P1 antagonist 8-phenyltheophylline. Adenosine increased the cAMP content of type II cells while ATP had little effect. The effects of ATP and terbutaline were additive while those of adenosine and terbutaline were not. These data show that ATP and adenosine stimulate phosphatidylcholine secretion via different mechanisms. Therefore, the effect of ATP is not mediated via catabolism to adenosine. Metabolically resistant analogs of ATP also stimulated secretion in a concentration-dependent manner although none were as potent as ATP. The order of potency was ATP greater than beta,gamma-methylene ATP = 2-methylthio ATP = 2-deoxy ATP greater than or equal to 8-bromo ATP greater than alpha,beta-methylene ATP. The facts that ATP analogs also stimulate secretion and that the effect of ATP was antagonized by alpha,beta-methylene ATP suggest that the stimulatory effect of ATP is mediated by the P2 purinoceptor.
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PMID:Functional evidence for involvement of P2 purinoceptors in the ATP stimulation of phosphatidylcholine secretion in type II alveolar epithelial cells. 283 Sep 2

Transmembrane signaling by chemoattractants in leukocytes appears to require activation of phosphoinositide metabolism with subsequent generation of the second messenger substances, inositol(1,4,5)trisphosphate and diacylglycerol. In addition, previous studies have shown that conditions which lead to an intracellular increase in S-adenosylhomocysteine (AdoHcy), a by-product and competitive inhibitor of S-adenosylmethionine-mediated methylation reactions, inhibit all chemoattractant-mediated functions of leukocytes, suggesting that AdoHcy also interferes with chemoattractant transmembrane signaling. In the present study, we determined whether AdoHcy altered the metabolism of phosphoinositides in human polymorphonuclear leukocytes. Treatment of 32P-labeled polymorphonuclear leukocytes with the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, plus exogenous adenosine and L-homocysteine thiolactone, conditions which cause an increase in AdoHcy, produced as much as a 37% decrease in the amount of [32P]phosphatidylinositol 4-monophosphate associated with the cells. The formation of inositol bisphosphate was inhibited by as much as 45% by erythro-9-(2-hydroxy-3-nonyl)adenine, adenosine, and L-homocysteine thiolactone suggesting decreased availability of phosphatidylinositol 4-monophosphate. In support of this, AdoHcy, in concentrations ranging from 0.01 to 0.1 mM, inhibited the transfer of gamma-32P from gamma-[32P] ATP to phosphatidylinositol (PtdIns). The inhibition of PtdIns kinase was competitive with an apparent Ki for AdoHcy of 43 microM. Increased intracellular AdoHcy reduced chemoattractant-mediated increases in inositol(1,4,5)trisphosphate formation suggesting abrogation of transmembrane signaling. These findings for the first time demonstrate that AdoHcy is a competitive inhibitor of PtdIns kinase and thus a regulator of the phosphoinositide pathway.
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PMID:Inhibition of phosphoinositide metabolism in human polymorphonuclear leukocytes by S-adenosylhomocysteine. 283 Nov 94

1. The activities of ecto- and cytosolic 5'-nucleotidase (EC 3.1.3.5), adenosine kinase (EC 2.7.1.20), adenosine deaminase (EC 3.5.4.4) and AMP deaminase (EC 3.5.4.6) were compared in ventricular myocardium from man, rats, rabbits, guinea pigs, pigeons and turtles. The most striking variation was in the activity of the ecto-5'-nucleotidase, which was 20 times less active in rabbit heart and 300 times less active in pigeon heart than in rat heart. The cytochemical distribution of ecto-5'-nucleotidase was also highly variable between species. 2. Adenosine formation was quantified in pigeon and rat ventricular myocardium in the presence of inhibitors of adenosine kinase and adenosine deaminase. 3. Both adenosine formation rates and the proportion of ATP catabolized to adenosine were greatest during the first 2 min of total ischaemia at 37 degrees C. Adenosine formation rates were 410 +/- 40 nmol/min per g wet wt. in pigeon hearts and 470 +/- 60 nmol/min per g wet wt. in rat hearts. Formation of adenosine accounted for 46% of ATP plus ADP broken down in pigeon hearts and 88% in rat hearts. 4. The data show that, in both pigeon and rat hearts, adenosine is the major catabolite of ATP in the early stages of normothermic myocardial ischaemia. The activity of ecto-5'-nucleotidase in pigeon ventricle (16 +/- 4 nmol/min per g wet wt.) was insufficient to account for adenosine formation, indicating the existence of an alternative catabolic pathway.
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PMID:Absolute rates of adenosine formation during ischaemia in rat and pigeon hearts. 283 26

Our recent studies have indicated that release of ATP/ADP from platelets causes enhanced O2-. responses in stimulated neutrophils. The current investigations were designed to provide further details of this phenomenon, to determine the structure-function correlates of the adenine compounds, and to assess if the results might be explained by the formation of a single metabolic product of ATP. ATP, ADP, AMP and adenosine enhanced O2-. responses of rat neutrophils stimulated with immune complexes or formyl chemotactic peptide (FMLP) but had no effect on responses of phorbol ester-stimulated neutrophils. Similar results were obtained in human neutrophils stimulated with immune complexes; when FMLP was the agonist, the results were divergent: ATP and ADP enhanced the responses, whereas AMP and adenosine were inhibitory. In structure-function studies, hydrolytically resistant forms of ATP (and other adenine nucleotides) containing blocked or cross-linked phosphate groups were active, suggesting that hydrolysis of these compounds to a common metabolic product is not required for their effects on O2-. responses. In contrast, other chemical modifications of the ribose ring or adenine base of ATP resulted in greatly diminished activity. To further pursue the question of whether metabolism of the adenine compounds via the adenosine pathway was related to the observed effects on O2-. responses, addition to rat neutrophils of inhibitors of adenosine deaminase, S-adenosyl homocysteine hydrolase, or xanthine oxidase failed to reproduce or augment the enhancement effects of the adenine compounds on O2-. responses, suggesting that metabolism of the adenine compounds to a common product may not be a requirement for the observed effects. Although the manner by which the adenine compounds affect O2-. responses is not known, the data suggest that adenosine and adenine nucleotides have important regulatory effects on oxygen radical responses of stimulated neutrophils.
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PMID:Regulatory effects of adenosine and adenine nucleotides on oxygen radical responses of neutrophils. 283 59

Of the various species of cellular 5'-nucleotidases, membranous, lysosomal and cytosolic, only the latter are likely to play a role in the physiologic dephosphorylation of the 5'-nucleoside monophosphates present in the cytoplasm. The necessity to preserve cellular ATP renders a strict control of the dephosphorylation as well as of the deamination of AMP mandatory, because both nucleotides are maintained in equilibrium by adenylate kinase. Our studies of cytosolic purine 5'-nucleotidases purified from rat liver and from human erythrocytes, reviewed in this presentation, have shown that both display complex kinetic properties. Both enzymes have markedly higher affinities for IMP and for GMP than for AMP. In addition, they are stimulated by nucleoside triphosphates, among them ATP and GTP, and inhibited by Pi. The erythrocytic purine 5'-nucleotidase is also stimulated by glycerate 2,3-bisphosphate. It could thus be expected that under conditions of ATP and GTP breakdown, particularly when accompanied by an increase in Pi, the dephosphorylation of AMP would be curtailed. To verify this hypothesis, experiments were performed with isolated rat hepatocytes and with human red blood cells. The rate of dephosphorylation of AMP was measured by following time-wise the production of adenosine in the presence of coformycin (or deoxycoformycin) and 5-iodotubercidin. The coformycins inhibit the deamination of adenosine into inosine by adenosine deaminase, and 5-iodotubercidin inhibits the recycling of adenosine into AMP by adenosine kinase. Upon induction of ATP catabolism by the addition of fructose to isolated rat hepatocytes, the dephosphorylation of AMP was nearly completely suppressed. In accordance with these results, the activity of the rat liver cytosolic 5'-nucleotidase, assayed in the presence of concentrations of substrate and effectors mimicking those measured in intact cells following the addition of fructose, was decreased as compared to control conditions. In hepatocytes in which ATP catabolism was induced by suppression of oxygen, the rate of dephosphorylation of AMP increased about 3-fold. However, in contradiction with these data, the activity of the cytosolic 5'-nucleotidase, measured under conditions mimicking anoxia, decreased markedly. In human erythrocytes, dephosphorylation of AMP did not occur under physiologic conditions, but proceeded when ATP catabolism was induced by glucose lack or by alkalinization. The rate of dephosphorylation of AMP was 3-fold higher during glucose deprivation than under alkaline conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytosolic purine 5'-nucleotidases of rat liver and human red blood cells: regulatory properties and role in AMP dephosphorylation. 285 49

The metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine were studied to elucidate the biochemical basis for their known cytotoxicities. 2-Azaadenosine is a known substrate for adenosine kinase. That 2-azahypoxanthine is a substrate for hypoxanthine (guanine) phosphoribosyltransferase is shown by the observations that, in cell-free fractions from HEp-2 cells supplemented with 5-phosphoribosyl-1-pyrophosphate, 2-azahypoxanthine inhibited the conversion of hypoxanthine to IMP but not the conversion of adenine to AMP, and hypoxanthine, but not adenine, inhibited the conversion of 2-azahypoxanthine to 2-azaIMP. [8-14C]2-Azahypoxanthine was synthesized from [8-14C]hypoxanthine via [2-14C]-4-amino-5-imidazolecarboxamide. In HEp-2 cells in culture, the principal metabolite of [8-14C]-2-azahypoxanthine was 2-azaATP; there was no detectable 14C in deoxynucleotides or in DNA or RNA fractions. 2-Azaadenosine was much more toxic than 2-azahypoxanthine, and, when used in the presence of an adenosine deaminase inhibitor, 2'-deoxycoformycin, was converted in HEp-2 cells to 2-azaATP in amounts that exceeded those of ATP in control cells. The pool of ATP was reduced by as much as 75% as 2-azaATP accumulated. In a short-term experiment (4 hr), 2-azaadenosine selectively reduced the pools of adenine nucleotides, whereas 2-azahypoxanthine reduced the pools of guanine nucleotides selectively. Both 2-azahypoxanthine and 2-azaadenosine inhibited the incorporation of formate into purine nucleotides and were without effect on the conversion of thymidine and uridine to nucleotides. 2-Azahypoxanthine inhibited the incorporation of thymidine into macro-molecules but not that of uridine or leucine; 2-azaadenosine inhibited the incorporation of all three of these precursors non-selectively. 2-AzaIMP inhibited IMP dehydrogenase competitively with IMP (Ki = 66 microM). The difference in effects of 2-azahypoxanthine and 2-azaadenosine perhaps may be due to the production, from 2-azahypoxanthine but not from 2-azaadenosine + 2'-deoxycoformycin, of 2-azaIMP, which inhibits synthesis of guanine nucleotides and thereby results in inhibition of DNA synthesis. Specific sites of action for 2-azaadenosine are yet undefined.
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PMID:Metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine. 285 58

A rapid enzymatic assay method for ammonia was developed by using glutamine synthetase from glutamate-producing bacteria together with pyruvate kinase, lactate dehydrogenase, and NADH. The time required for determination of 25 nmol of ammonia was 5 min with 1 unit of glutamine synthetase, as opposed to 14-30 min with 1 unit of glutamate dehydrogenases from various sources. The present method was used to determine ammonia in serum, microbiol-culture broth, and waste water. The method can be modified for spectrophotometry in the visible region by substituting pyruvate oxidase, peroxidase, and appropriate chromogens for lactate dehydrogenase and NADH. With 4-aminoantipyrine (4AA) and phenol, and with 4AA and N-ethyl-N-2-hydroxyethyl-m-toluidine as chromogens, the sensitivity of ammonia determination was 0.65 and 1.7 times that with glutamate dehydrogenase, respectively. The present method was also applicable to the continuous detection of the activity of some ammonia-forming enzymes such as guanase, adenosine deaminase, and urease and to the determination of 0.5-30 microM ATP-ADP after some modification of the mixture.
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PMID:A rapid assay method for ammonia using glutamine synthetase from glutamate-producing bacteria. 288 29

Agents that cause the accumulation of DNA strand breaks are directly cytotoxic to non-dividing normal human peripheral blood lymphocytes, and to chronic lymphocytic leukemia (CLL) cells. Activation of poly(ADP-ribose) polymerase (ADPRP), and the resultant consumption of NAD, play an essential role in mediating the toxicity of these agents. Human peripheral blood lymphocytes contain a substantial number of alkali-sensitive DNA sites, reflecting ongoing DNA strand breakage and repair. However, resting lymphocytes have a limited capacity to synthesize NAD. Pulse-chase experiments indicate that approximately 75% of their NAD turnover is due to ADPRP activity. Exposure of the cells in vitro to deoxyadenosine, or to 2-chlorodeoxyadenosine (CdA, an adenosine deaminase resistant deoxyadenosine congener), caused an increase in DNA strand breaks, rapid NAD consumption, ATP depletion and cell death. Supplementation of the medium with inhibitors of poly(ADP-ribose) polymerase blocks the fall in cellular NAD and ATP, and protects the lymphocytes from the toxicity of DNA damaging agents. Slowly dividing malignant lymphocytes from patients with CLL are also susceptible to lethal NAD depletion following DNA damage. 2-chlorodeoxyadenosine (CdA) induced massive DNA strand break formation in CLL cells in vitro and a fall in NAD and ATP pools. In an initial clinical trial, several CLL patients, and two patients with hairy cell leukemia, have responded to treatment with CdA, with minimal toxicity. Thus, the suicidal activation of ADPRP in response to DNA damage has been rationally exploited in the treatment of chronic lymphoid malignancies.
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PMID:Programmed cell death and adenine deoxynucleotide metabolism in human lymphocytes. 290 67

The importance of intact adenosine deaminase (ADA) activity in the generation of superoxide anion by xanthine oxidase has been disputed in studies using human neutrophils or mouse macrophages. The latter demonstrated a positive correlation between ADA activity and superoxide production during phagocytosis. The immunodeficiency in inherited ADA deficiency was related to a defect in this process. Since there is considerable interspecies variation in the tissue distribution of xanthine oxidase, the metabolism of [8-14C]deoxyadenosine (dAR), the toxic metabolite which accumulates in inherited ADA deficiency, was investigated in human peritoneal macrophages. Evaluation of the distribution of radiolabel in both cell and medium demonstrated that human macrophages with intact ADA metabolize dAR under physiological conditions to deoxyinosine and hypoxanthine exclusively. The hypoxanthine is further metabolized within the cell to ATP and GTP, via IMP. No xanthine or uric acid could be detected, confirming that in human macrophages xanthine oxidase activity is insignificant, as it is in most other human cells and tissues, except liver and intestinal mucosa. Thus production of superoxide radicals in such cells via this route would be impossible, and consequently unaffected either by ADA deficiency or the xanthine oxidase inhibitor allopurinol.
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PMID:Superoxide radicals, immunodeficiency and xanthine oxidase activity: man is not a mouse! 298 25

Zymosan particle-stimulated beta-galactosidase secretion by mouse peritoneal macrophages was found to be inhibited by micromolar concentrations of adenosine, AMP, ADP, and ATP. Inhibition by all four agents was increased to approximately 80% by adding erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 10 microM) an adenosine deaminase inhibitor, to the incubation medium. The inhibition of lysosomal enzyme secretion by ATP, ADP, and AMP was reversed by adding alpha, beta -methylene ADP (100 microM), a 5'-nucleotidase inhibitor, to the incubation medium. Inhibition by adenosine, however, was unaffected by alpha, beta -methylene ADP indicating that the inhibition by AMP, ADP, and ATP only occurred after they had been converted to adenosine by cell surface phosphohydrolases, including 5'-nucleotidase. Theophylline, a competitive antagonist of the binding of adenosine to plasma membrane adenosine receptors, failed to reverse the inhibitory effect of adenosine indicating the probable site of adenosine action to be intracellular. Other purine nucleosides, e.g., guanosine, and several purine and ribosemodified structural analogues of adenosine also inhibited zymosan-stimulated beta-galactosidase secretion, while xanthosine and certain pyrimidine nucleosides, e.g., thymidine, were inactive in this respect.
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PMID:Regulation of macrophage lysosomal secretion by adenosine, adenosine phosphate esters, and related structural analogues of adenosine. 298 3


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