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

---

Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies with purified enzymes have shown that 2'-deoxycoformycin (dCF) is a potent and selective inhibitor of adenosine deaminase (ADA). Specificity of dCF's effects on adenosine metabolism in intact human skin fibroblasts was investigated by examining the isotopic flux from exogenous [14C] adenosine to metabolic products in hypoxanthine phosphoribosyltransferase deficient (HPRT-) cells which cannot recycle hypoxanthine. Apparent ADA activity (as estimated by isotopic flux to inosine and hypoxanthine) was profoundly inhibited by dCF (with at least 50% inhibition at 10(-8) M and 95% inhibition at 10(-5) M dCF). The degree of inhibition was similar at various exogenous adenosine concentrations ranging from 1 to 400 microM. Some inhibition of isotopic flux to adenine nucleotides (an ADA independent process in HPRT- cells) could be demonstrated, but only in media containing high concentrations of adenosine. Even at 400 microM adenosine, the highest concentration employed, isotopic flux to adenine nucleotides was unaffected by concentrations of dCF below 10(-6) M, and only 30% inhibition was achieved with 10(-5) M dCF. Inhibition of adenosine phosphorylation to AMP appears to be the most likely explanation for dCF inhibition of isotopic flux from [14C] adenosine to adenine nucleotides, probably due to substrate inhibition of adenosine kinase by high levels of intracellular adenosine produced when ADA is inhibited by dCF. No evidence for dCF inhibition of either adenosine transport or phosphorylations within the adenine nucleotide pool (from AMP to ADP or from ADP to ATP) was found. Thus, at physiological levels of exogenous adenosine (0.03 to 2.6 microM), dCF appears to be a potent and highly specific inhibitor of ADA in human skin fibroblasts.
...
PMID:Specificity of 2'-deoxycoformycin inhibition of adenosine metabolism in intact human skin fibroblasts. 348 39

The synthesis and characterization of 8-amino-6-fluoro-9-beta-D-ribofuranosyl-9H-purine (3a) are presented. This compound is a substrate for adenosine deaminase and adenosine kinase. In L1210 cells 3a is converted to 8-aminoinosine monophosphate (4b), apparently by the action of AMP deaminase on the monophosphate of 3a, as well as to the triphosphate derivative of 3a. Pentostatin was used to inhibit adenosine deaminase, and coformycin was used to inhibit AMP deaminase in experiments designed to delineate the metabolic fate of 3a. Pentostatin was without influence on the cytotoxicity of 3a, but coformycin potentiated the cytotoxicity. The potentiation was associated with an increased cellular concentration of phosphates of 3a and a decreased concentration of 4b.
...
PMID:Synthesis and biochemical properties of 8-amino-6-fluoro-9-beta-D-ribofuranosyl-9H-purine. 348 38

Attempts to identify mechanisms by which calcium antagonists might influence intracellular metabolism have not yet yielded conclusive findings. In this study bepridil, verapamil, nifedipine, and nisoldipine were found to have no influence on the rate of rat heart myosin adenosine triphosphatase or the calcium dependence of myofibrillar adenosine triphosphatase. None of these calcium antagonists alters the rate of reaction of any of the adenine nucleotide catabolic or adenosine salvage enzymes, adenylate kinase, creatine kinase, adenosine kinase, adenosine deaminase, or 5' nucleotidase, in extracts of rat heart. All four compounds, however, reduced, apparently in a non-specific manner, the rate of uptake of adenosine by myocytes isolated from rat heart. It is concluded that calcium antagonists may, through intercalation with the sarcolemmal membrane, inhibit efflux of adenosine formed by catabolism of adenine nucleotides in ischaemic myocytes. This might offer therapeutic advantage since the intracellular concentration of adenosine would thereby be increased, allowing an increased rate of incorporation of adenosine into the adenosine triphosphate pool in reoxygenated myocardium.
...
PMID:Calcium antagonists and adenine nucleotide metabolism in rat heart. 349 85

The correlation between the metabolic processing of 3'-deoxyadenosine N1-oxide (3'-dANO) in vitro and its effect on tumor growth in vivo has been investigated in seven different strains of Ehrlich ascites tumor cells. The metabolism of 3'-dANO is initiated by reduction to 3'-deoxyadenosine (3'-dA). This process is the rate-limiting process. The 3'-dA does not accumulate, but is converted to 3'-deoxyadenosine triphosphate (3'-dATP) or 3'-deoxyinosine (3'-dI). The ratio between 3'-dATP and 3'-dI inosine corresponds to the ratio between the activities of adenosine kinase and adenosine deaminase in the cell. Two of the cell lines were markedly inhibited by 3'-dANO in vivo. In these cells the accumulation of 3'-dATP was 1.4-2.2 nmol/h per mg cells, which accounts for the major part of the metabolized 3'-dANO. Five of the cell lines were not inhibited by 3'-dANO and the formation of 3'-dATP was 5-10 times less in these than in the sensitive strains. The low level of 3'-dATP is caused primarily by a low ratio between the activities of adenosine kinase and adenosine deaminase, which is 15 time less than in the sensitive cell lines. The rate of reduction of 3'-dANO seems to be of minor importance. These results indicate a correlation between the inhibition of tumor growth by 3'-dANO and the ability of the cell to accumulate 3'-dATP from 3'-dANO and show that this conversion is determined solely by the rate of reduction of 3'-dANO (3'-dANO reductase activity) and the ratio between the activities of adenosine kinase and adenosine deaminase in the cell. Consequently, the estimation of these enzyme activities in cell lysate of a given tumor can be used to predict whether the tumor is susceptible to inhibition by 3'-dANO.
...
PMID:Studies on the mechanism of cytotoxicity of 3'-deoxyadenosine N1-oxide in different strains of Ehrlich ascites tumor cells. 349 46

By means of selective inhibitors of adenosine deaminase and adenosine kinase, the contributions of two competing pathways for the breakdown of adenosine nucleotides in erythrocytes of man were examined. Under nearly physiological conditions in vitro the main pathway for the irreversible breakdown proceeds from AMP via IMP and inosine to hypoxanthine. Its rate amounts to 12 mumol AMP/l cells X h. At the same time about three times as much AMP, about 40 mumol/l cells X h, are degraded by way of dephosphorylation to adenosine. However, this pathway does not contribute significantly to the production of hypoxanthine, since the adenosine formed is rephosphorylated by adenosine kinase. Both AMP and IMP are dephosphorylated by an unspecific cytosolic acid phosphatase, the maximal activity of which amounts to 660 mumol nucleotide/l cells X h.
...
PMID:Degradation of AMP in erythrocytes of man. Evidence for a cytosolic phosphatase activity. 349 48

Rat hepatoma cells amplified for adenosine deaminase (ADA) gene sequences show the amplified DNA on large, homogeneously staining regions (HSRs). The amplified cells are stable in the absence of selection for 12 mo without loss of ADA activity or gene sequences. However, in hybrids formed between an amplified cell line with a prominent HSR and a nonamplified cell line, rapid loss of ADA activity, as well as gene sequences, occurs. Karyotype analyses of the hybrids indicate that the HSR structures are no longer visible in a large percentage of the hybrid metaphase spreads and appear to have been replaced by DNA structures that resemble double minutes. Our data provide evidence that the extent of the breakdown of the HSR in the hybrids may be affected by the presence of an active adenosine kinase or the level of ATP in the cells and additional unidentified factors are present in the hybrids that affect the integrity of the HSR structure. There is no evidence for a specific trans-acting factor in nonamplified cells that regulates gene amplification.
...
PMID:Destabilization of the adenosine deaminase gene sequences in rat-rat somatic cell hybrids. 358 19

The turnover of the adenine nucleotide pool, the pathway of the degradation of AMP and the occurrence of recycling of adenosine were investigated in isolated chicken hepatocytes, in which the adenylates had been labelled by prior incubation with [14C]adenine. Under physiological conditions, 85% of the IMP synthesized by the 'de novo' pathway (approx. 37 nmol/min per g of cells) was catabolized directly via inosine into uric acid, and 14% was converted into adenine nucleotides. The latter were found to turn over at the rate of approx. 5 nmol/min per g of tissue. Inhibition of adenosine deaminase by 1 microM-coformycin had no effect on the formation of labelled uric acid, indicating that the initial degradation of AMP proceeds by way of deamination rather than dephosphorylation. Inhibition of adenosine kinase by 100 microM-5-iodotubercidin resulted in a loss of labelled ATP, demonstrating that adenosine is normally formed from AMP but is recycled. Unexpectedly, 5-iodotubercidin did not decrease the total concentration of ATP, indicating that the loss of adenylates caused by inhibition of adenosine kinase was nearly completely compensated by formation of AMP de novo. Anoxia induced a greatly increased catabolism of the adenine nucleotide pool, which proceeded in part by dephosphorylation of AMP. On reoxygenation, the formation of AMP de novo was increased 8-fold as compared with normoxic conditions. The latter results indicate the existence of adaptive mechanisms in chick liver allowing, when required, channelling of the metabolic flux through the 'de novo' pathway, away from the uricotelic catabolic route, into the synthesis of adenine nucleotides.
...
PMID:Adenine nucleotide metabolism in isolated chicken hepatocytes. 359 67

7-Amino-3-(2'-deoxy-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (2'-deoxyformycin A) was synthesized from formycin A by a sequence consisting of (i) 3',5'-cyclosilylation with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, (ii) 2'-acylation with phenoxythiocarbonyl chloride and 4-(N,N-dimethylamino)pyridine, (iii) N-trimethylsilylation with hexamethyldisilazane, (iv) reduction of the 2'-O-phenoxythiocarbonyl group with tri-n-butyltin hydride, and (v) desilylation with tetra-n-butylammonium fluoride. 2'-Deoxyformycin A was a potent inhibitor of the in vitro growth of S49 lymphoma, a murine tumor of T-cell origin. The IC50 of 2'-deoxyformycin A against S49 cells was 10-15 microM, whereas that of 2'-deoxyadenosine (dAdo) under the same conditions (72-h incubation in medium containing heat-inactivated horse serum) was 180 microM. In the presence of 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to block intracellular adenosine deaminase (ADA) activity, 2'-deoxyformycin A and dAdo both gave IC50's of 5-10 microM. When assayed against a mutant S49 subline lacking adenosine kinase (AK) or a subline with a combined deletion of AK and deoxycytidine kinase (dCK), 2'-deoxyformycin A in combination with 10 microM EHNA was inactive at concentrations of up to 50 microM. Similar lack of activity against kinase-deficient cells was shown by formycin A. Thus, phosphorylation of 2'-deoxyformycin A appears to be required for biological activity and is probably catalyzed by AK rather than dCK. 2'-Deoxyformycin A and related 2'-deoxyribo-C-nucleoside analogues of the purine type may be of interest as potential T-cell specific cytotoxic agents.
...
PMID:Improved synthesis of 2'-deoxyformycin A and studies of its in vitro activity against mouse lymphoma of T-cell origin. 387 61

Analysis of the response of baby hamster kidney cells to adenosine in the presence of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine has revealed two distinct mechanisms of toxicity. The first is apparent at low concentrations of adenosine (less than 5 microM) and is dependent upon the presence of a functional adenosine kinase. The initial toxicity is abolished by uridine, is unrelated to the inhibition of ribonucleotide reductase, and is accompanied by a decrease in the size of the pyrimidine nucleotide pool. Toxicity at higher concentrations of adenosine is adenosine kinase independent and is potentiated by homocysteine thiolactone. An elevation in the intracellular level of S-adenosylhomocysteine, which was observed following treatment with higher concentrations of adenosine (greater than 10 microM), is believed to mediate toxicity at these levels. Interestingly, BHK cells were resistant to intermediate levels of adenosine. The mechanism of resistance is currently unknown, but appears unrelated to a lack of inhibition of adenosine deaminase. It is proposed that substrate inhibition of adenosine kinase may be a determinant of this property.
...
PMID:An analysis of multiple mechanisms of adenosine toxicity in baby hamster kidney cells. 390 94

The exact pathway whereby the initial catabolism of the adenine nucleotides proceeds from AMP and the possibility of a recycling of adenosine were investigated in human erythrocytes. Adenine nucleotide catabolism, reflected by the production of hypoxanthine, is very slow under physiologic conditions and can be greatly increased by suppression of glucose or alkalinization of the medium. Experiments with inhibitors of adenosine deaminase and adenosine kinase demonstrated that under physiologic conditions the initial catabolism of AMP proceeds by way of a deamination of AMP, followed by dephosphorylation of inosine monophosphate, and that no recycling occurs between AMP and adenosine. Under glucose deprivation, approximately 75% of the 20-fold increase of the catabolism of the adenine nucleotides proceeded by way of a dephosphorylation of AMP followed by deamination of adenosine, and a small recycling of this nucleoside could be evidenced. Inhibition of adenosine transport showed that the dephosphorylation of AMP occurred intracellularly. When the incubation medium was alkalinized in the presence of glucose, the 15-fold increase in the conversion of AMP to hypoxanthine proceeded exclusively by way of AMP deaminase but a small recycling of adenosine could also be evidenced. The threefold elevation of intraerythrocytic inorganic phosphate (Pi) during glucose deprivation and its 50% decrease during alkalinization as well as experiments in which extracellular Pi was modified, indicate that the dephosphorylation of red blood cell AMP is mainly responsive to variations of AMP, whereas its deamination is more sensitive to Pi.
...
PMID:Pathways of adenine nucleotide catabolism in erythrocytes. 394 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---