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 effect of adenosine was tested on the energetic metabolism of fed rat liver cells after isolation. The cells were incubated in a buffered saline medium with glucose (5 mM) and adenosine (1 mM) for 30 minutes at 37 degrees C. This increased the concentration of the adenylic nucleotides ATP (+57 per cent, ADP (+39 per cent). Cyclic AMP was increased (+50 per cent) and the intracellular inorganic phosphate decreased (-22 per cent). These changes were accompaned by a decrease of glycogenolysis, glucose consumption and lactate production. Measurement of glycolytic intermediates showed decreased concentrations of fructose 1,6-bis-phosphate and 3-phosphoglycerate proportional to the increase in ATP concentration. The near-equilibrium of the glyceraldehyde 3-phosphate dehydrogenase-phosphoglycerate kinase system was not modified by adenosine. The decrease of the NAD+/NADH ratio along with the increase of the ATP/ADP X PO4 ratio explains the decrease of 3-phosphoglycerate. The decrease in glucose consumption can be explained by the cross over at the phosphofructokinase stage with the decrease of fructose 1,6-bisphosphate. The major part of adenosine was deaminated as indicated by an increase in the production of ammonia and urea. The effects of inosine, or adenosine along with an inhibitor of adenosine deaminase (pentostatin) suggest that adenosine acts on the glucose consumption through adenylic nucleotides. However the increase of the adenylic nucleotide level cannot totally explain the other metabolic changes: decrease of the NAD+/NADH cytoplasmic ratio, constancy of this ratio in mitochondria, decrease of gluconeogenesis from lactate. A direct action of adenosine can therefore be expected.
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PMID:The influence of adenosine on intermediary metabolism of isolated hepatocytes. 23 80

A simple, rapid (2 hours), fluorescent test for the activity of blood adenosine deaminase (ADA) is described. The test which can be performed on both heparinized and dried blood, is based on the conversion of adenosine to inosine and ammonium in the presence of ADA. The enzyme activity is visually estimated by the oxidation of NADH (fluorescent) to NAD+ (non-fluorescent) in a coupled reaction with glutamate dehydrogenase. The disappearance of fluorescence indicates ADA activity in the sample. The advantages are discussed of the use of this test for the study of the autosomal recessive severe combined immunodeficiency.
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PMID:A simple rapid fluorescent assay for adenosine deaminase activity. 31 78

The adenosine deaminase inhibitors deoxycoformycin and erythro-9-(2-hydroxy-3 nonyl) adenine (EHNA) induce single-strand DNA breaks in cultured human lymphocytes. Deoxycoformycin produced a significant number of strand breaks (4-fold increase compared to controls) and EHNA induced strand breaks in a dose-dependent manner. Strand breaks stimulate repair by poly(ADP-ribosylation) which requires NAD+ as a cofactor. Niacin is a precursor of NAD+ and when preincubated with human lymphocytes prior to exposure to adenosine deaminase inhibitors, strand breakage was reduced significantly. The administration of niacin may represent an approach to decreasing the toxicity associated with these agents.
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PMID:Niacin prevents DNA strand breakage by adenosine deaminase inhibitors. 232 39

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

The metabolic changes induced by the deoxycoformycin inhibition of adenosine deaminase were studied in human erythrocytes incubated with nucleosides. 1 Adenosine nucleotide levels and glycolytic rate were increased by adenosine. 2 With deoxyadenosine, the cellular ATP level was reduced when dATP increased and the glycolytic rate was similarly enhanced. 3 The hypoxanthine production was equivalent in both cases. Our data demonstrate that human red cells are able to catabolize adenine deoxynucleotides into hypoxanthine, and the control of energy metabolism is not impaired by adenosine deaminase inhibition when PO identical to 4 and NAD+ are not limiting.
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PMID:Energy metabolism in adenosine deaminase-inhibited human erythrocytes. 348 57

The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
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PMID:Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency. 395 May 45

Autologous rosette-forming cells (ARFC) have been considered to be post-thymic precursor cells. Since thymocytes and peripheral T lymphocytes differ considerably in lactate dehydrogenase isoenzyme pattern and in activity of the enzymes of the purine metabolism, we investigated the enzyme profile in the ARFC. The L-lactate: NAD+ oxi-reductase analysis showed an isoenzyme pattern that closely resembled the pattern found in peripheral T lymphocytes and was totally different from the thymocytes. The levels of adenosine deaminase and purine nucleoside phosphorylase were identical to those found in the peripheral T lymphocytes and different from thymocytes. In our hands, the ARFC-enriched suspension contained predominantly OKT4+ and T mu+ lymphocytes. We propose that ARFC are a heterogeneous population encompassing all known subsets and cannot be considered a separate homogeneous entity.
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PMID:Enzyme analysis of autologous rosette-forming cells. 642 30

The aliphatic adenine analogues, D-eritadenine, L-eritadenine, L-threoeritadenine, and 9-(S)-(2,3-dihydroxypropyl)adenine [(S)DHPA] function as inhibitors/inactivators of purified S-adenosylhomocysteine (AdoHcy) hydrolase, but these compounds did not induce reduction of enzyme-bound NAD+. D-Eritadenine, L-eritadenine, (S)DHPA, and L-threo-eritadenine inactivated AdoHcy hydrolase in hepatocytes, and the efficiency decreased in the order mentioned. Concurrently, there was an increase in the AdoHcy content. The accumulation of AdoHcy in the presence of (S)DHPA was more pronounced than would be expected from the inactivation of enzyme activity, suggesting that this compound may function as a reversible inhibitor as well. Furthermore, the inactivation of the intracellular enzyme by (S)DHPA is remarkable in the light of the fact that this compound induces no inactivation of purified AdoHcy hydrolase, but merely functions as an inhibitor of the enzyme. At low concentration of D-eritadenine (less than 6 microM), a distinct lag period could be demonstrated before accumulation of AdoHcy occurred. This suggests that the AdoHcy hydrolase activity must be decreased below a certain level to cause an increase in cellular AdoHcy. None of the analogues tested completely inactivated AdoHcy hydrolase and a residual enzyme activity was observed. The adenosine deaminase inhibitor, 2'-deoxycoformycin, did not potentiate the effect of these compounds on AdoHcy catabolism. The inactive enzyme formed in the presence of aliphatic adenine analogues was not reactivated under conditions where the inactivation induced by 9-beta-D-arabinofuranosyladenine was reversible.
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PMID:The effect of aliphatic adenine analogues on S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase in intact rat hepatocytes. 649 10

In the isolated rat vas deferens stimulated at 0.2 Hz, [14C]labelled 5'-AMP, 5'-ADP and 5'-ATP (10 microM) inhibited twitch responses, were broken down to [14C]adenosine in the medium and incorporated into [14C]adenine ribonucleotides in the tissue. Pretreatment of tissues with 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBTGR), a potent inhibitor of adenosine transport, potentiated the presynaptic inhibitory action of these 5' nucleotides and reduced their incorporation in [14C]adenine nucleotides, but did not alter the appearance of [14C]adenosine in the medium. A series of 2', 3' and 5'-substituted adenine nucleotides (10 microM) inhibited the twitch responses of the vas deferens stimulated at 0.2 Hz. This effect was potentiated by NBTGR. Addition of exogenous adenosine deaminase very significantly reduced the inhibitory actions of adenosine, 5'-AMP, 5'-ADP and 5'-ATP and also reduced those of 2', 5'-ADP, NAD+ and dePCoA. The inhibitory actions of the other 2', 3' and 5' adenine nucleotides studied were not altered by exogenous adenosine deaminase. These results indicated that the presynaptic inhibitory actions of 5'-AMP, 5'-ADP and 5'-ATP in rat vas deferens predominantly result from their prior hydrolysis to adenosine whereas the 2', 3' and 5'-substituted adenine nucleotides appear to act mainly directly to inhibit transmitter release.
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PMID:Metabolism and presynaptic inhibitory activity of 2',3' and 5'-adenine nucleotides in rat vas deferens. 730 Sep 14

Postmitotic sympathetic neurons are known to undergo a programmed cell death (apoptosis) when they are deprived of nerve growth factor (NGF) or treated with arabinofuranosyl nucleoside antimetabolites. Here we report the existence of a biochemical mechanism for the induction of neuronal death by an endogenous nucleoside in the presence of NGF. In support of such a mechanism we show that 2-deoxyadenosine (dAdo) induces apoptosis in chick embryonic sympathetic neurons supported in culture by NGF, excess K+, phorbol 12,13-dibutyrate, or forskolin. Neuronal death was related to a dramatic increase in the dATP content of sympathetic neurons exposed to dAdo (34.96 +/- 5.98 versus 0.75 +/- 0.16 pmol/micrograms protein in untreated controls, n = 9), implicating dATP in the toxicity. Supportive evidence for a central role of dATP was gained by inhibition of kinases necessary for phosphorylation of dAdo. 5'-Iodotubercidin in nanomolar concentrations completely and dose-dependently inhibited formation of dATP and also protected against toxicity of submillimolar concentrations of dAdo in sympathetic neurons. Although some of these actions of dAdo were remarkably similar to those reported for human lymphoid cells, several were uniquely different. For example, [3H]dAdo was not transported into neurons by the nucleoside transporter, and therefore inhibition of the transporter (dilazep, nitrobenzylthioinosine) did not prevent neurotoxicity by dAdo. Precursors of pyrimidine synthesis (2'-deoxycytidine, uridine) or NAD+ synthesis (nicotinamide) were ineffective in protecting sympathetic neurons against dAdo toxicity. Finally, inhibition of adenosine deaminase by deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl) adenine did not potentiate the toxic effects of dAdo. Our results provide evidence for the first time that neuronal cells are as susceptible to nucleoside lethality as human lymphocytes are, and provide a new model to study the salvage pathway of deoxyribonucleosides in controlling neuronal populations through programmed cell death.
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PMID:Deoxynucleoside induces neuronal apoptosis independent of neurotrophic factors. 762 6


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