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)

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 work on adenosine transport has always had problems with the interference of adenosine metabolism, due to its high metabolic rate and because the enzymes involved are consistently present in most tissues. A new experimental model for studying adenosine transport in human erythrocyte ghosts is presented in this work: Human erythrocyte ghosts were sealed in the presence of erythro-3(2-hydroxynonyl)adenine and P1-P5-di(adenosine)5'-pentaphosphate, inhibitors of adenosine deaminase and adenosine kinase, respectively. These ghosts proved to lack adenosine metabolism when incubated in [U-14C]adenosine at 10 microM concentration at lack 37 degrees C for 60 min. Ghosts were 99.4% sealed in the correct orientation and had constant intracellular water volume. With these characteristics, the erythrocyte ghost preparation has many advantages for studying adenosine transport without adenosine metabolism interference. Adenosine transport was studied following the technique of W. R. Lieb and W. D. Stein [(1974) Biochim. Biophys. Acta 373, 165-177, 178-196.] Experiments to study Zero-trans influx and efflux, equilibrium exchange, and infinite-trans influx and efflux are presented. Adenosine transport did not behave linearly in any of these experimental procedures. Adenosine basic kinetic constants, calculated according to the procedure of Lieb and Stein, were R1----2 = 4.1 X 10(-4), R2----1 = 3.97 X 10(-4), Ree = 1.94 X 10(-4), Roo = 6.08 X 10(-4), K1----2 = 125.67 microM, and K2----1 = 84.36 microM. Lieb and Stein rejection criteria were used to distinguish a simple pore from a simple carrier. The data accumulated indicate that adenosine transport is carried out by a system that satisfies the criteria used for the simple carrier model. Asymmetric behavior was observed indicating lower affinity of the carrier for adenosine influx, although Vmax values for influx and efflux were similar.
...
PMID:The human erythrocyte ghost: a new experimental model for studying adenosine transport. 401 3

Adenosine (Ado, 10 microM) did not inhibit ADP-induced human platelet aggregation in whole blood. However, if the blood was preincubated with dipyridamole (10 microM), a potent inhibitor of the erythrocytic nucleoside transport system (NTS), Ado acted as a strong inhibitor of platelet aggregation. Similarly, Ado inhibited platelet aggregation in whole blood in the presence of other potent NTS inhibitors, dilazep (1 microM) and p-nitrobenzylthioinosine (NBMPR, 1 microM). RA 233 (10 microM), an analog of dipyridamole which is a potent inhibitor of platelet cAMP phosphodiesterase (PDE), did not evoke the Ado effect in whole blood. However, in platelet-rich plasma (PRP), RA 233 potentiated strongly Ado-mediated inhibition, whereas dipyridamole, dilazep and NBMPR were without activity. 5'-Methylthioadenosine (MTA), an Ado receptor antagonist, reversed the inhibition produced by a nucleoside transport system inhibitor plus Ado in whole blood. Dipyridamole (10 microM), dilazep (1 microM) or NBMPR (1 microM) blocked [14C]Ado (10 microM) uptake by blood cells in whole blood, whereas RA 233 (10 microM) was not effective. The combination of 2'-deoxycoformycin (dCF, 5 microM), a tight-binding inhibitor of adenosine deaminase (ADA), plus 5-iodotubercidin (ITu, 10 microM), a potent inhibitor of adenosine kinase (Ado kinase), gave comparable Ado-mediated inhibition of platelet aggregation in whole blood as was obtained when the blood was pretreated with dilazep. These studies suggest that the in vivo antiplatelet actions of drugs such as dipyridamole and dilazep result from their abilities to block erythrocytic Ado uptake and subsequent metabolism, thus elevating the extracellular steady-state concentration of the physiologically occurring, antiplatelet agent, Ado.
...
PMID:Role of adenosine uptake and metabolism by blood cells in the antiplatelet actions of dipyridamole, dilazep and nitrobenzylthioinosine. 406 70

1 The cardiovascular actions of 23 adenosine analogues have been examined in anaesthetized open thorax dogs; the analogues were substituted in the 2-position of the purine ring, or in the exocyclic amino group, or were modified in the imidazole or sugar rings.2 The effects of these compounds on coronary blood flow, peripheral blood pressure, and heart rate were compared with those of adenosine.3 9-beta-D-Arabinofuranosyladenine had no cardiovascular action; the other analogues on intra-atrial administration caused an immediate increase in coronary blood flow, the magnitude and duration of which varied with the structures of the analogues.4 2-Fluoro-, 2-bromo-, 2-isobutylthio-, 2-ethylamino-, and 5'-deoxy-5'-chloro- adenosines had coronary dilator potencies equal to or greater than that of adenosine. No relationship was found between the dilator potency of the adenosine analogues and their duration of coronary dilator action.5 The coronary dilator action of adenosine was potentiated by inosine, 9-beta-D-arabinofurano-syladenine, tubercidin, N(6)-methyladenosine and 2-trifluoromethyl-N(6)-methyladenosine.6 There was no correlation between the substrate specificities of the shorter-acting analogues for adenosine deaminase or adenosine kinase and their duration of coronary dilator action.7 It is proposed that in the anaesthetized dog, uptake into tissues is a more important mode of removal of adenosine and adenosine analogues from the vascular system than inactivation by adenosine deaminase, that the duration of coronary dilator action of the analogues is related primarily to their specificity for the carrier which mediates adenosine uptake, and that the adenosine carrier is not associated with kinase action.
...
PMID:Studies on the coronary dilator actions of some adenosine analogues. 436 49

Purine-requiring mutants of Salmonella typhimurium LT2 containing additional mutations in either adenosine deaminase or purine nucleoside phosphorylase have been constructed. From studies of the ability of these mutants to utilize different purine compounds as the sole source of purines, the following conclusions may be drawn. (i) S. typhimurium does not contain physiologically significant amounts of adenine deaminase and adenosine kinase activities. (ii) The presence of inosine and guanosine kinase activities in vivo was established, although the former activity appears to be of minor significance for inosine metabolism. (iii) The utilization of exogenous purine deoxyribonucleosides is entirely dependent on a functional purine nucleoside phosphorylase. (iv) The pathway by which exogenous adenine is converted to guanine nucleotides in the presence of histidine requires a functional purine nucleoside phosphorylase. Evidence is presented that this pathway involves the conversion of adenine to adenosine, followed by deamination to inosine and subsequent phosphorolysis to hypoxanthine. Hypoxanthine is then converted to inosine monophosphate by inosine monophosphate pyrophosphorylase. The rate-limiting step in this pathway is the synthesis of adenosine from adenine due to lack of endogenous ribose-l-phosphate.
...
PMID:Metabolism of exogenous purine bases and nucleosides by Salmonella typhimurium. 492 5

Low concentrations (10-50 microM) of adenosine (EC50 = 17 microM) or chloroadenosine (EC50 = 23 microM) prevent the division of PC12 cells. This inhibition is not mimicked by guanosine, inosine, 3',5' dideoxyadenosine, phenylisopropyladenosine, or adenylylimidodiphosphate. The growth inhibition is not relieved by addition of uridine or deoxycytidine, nor is it potentiated by homocysteine thiolactone. Inhibition of adenosine uptake does not inhibit adenosine-dependent growth arrest. PC12 variants that are deficient in adenosine kinase are as sensitive as wild-type cells to the growth-inhibitory effects of adenosine. These experiments suggest that adenosine prevents cell division at an adenosine receptor rather than acting after being metabolically altered. The adenosine receptor that inhibits cell division does not appear to be the adenosine receptor that stimulates adenylate cyclase for these reasons: (1) phenylisopropyladenosine, which is a potent agonist of this receptor, does not inhibit cell division; (2) 3',5' dideoxyadenosine does not antagonize the effect of adenosine on cell division; and (3) theophylline does not affect growth inhibition by adenosine. Thus, these experiments suggest the existence of a second adenosine receptor that can inhibit cell division. Adenosine also promotes the morphological differentiation of PC12 cells. In the presence of the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA), adenosine causes the formation of short neurites (one-half to one and one-half cell diameters in length). Adenosine also increases the rate of neurite formation of both long and short neurites in response to NGF.
...
PMID:Adenosine inhibits cell division and promotes neurite extension in PC12 cells. 608 75

Purine bases and purine nucleosides pass the cell membrane by facilitated diffusion. For purine bases two different carrier proteins seem to exist. Purine bases are trapped intracellularly immediately after passage of the cell membrane by the action of purine phosphoribosyltransferases (PRTs). Comparison of kinetic data of transport and intracellular enzyme reactions shows that intracellular metabolism is rate limiting for the whole uptake process. Since phosphate stimulates the uptake of bases, limited availability of phosphoribosylpyrophosphate (PRPP) might play a regulatory role. Purine nucleosides apparently enter cells via a common carrier. Of the nucleosides under investigation, only adenosine was taken up in significant amounts. Uptake of adenosine is mainly determined by the ratio of adenosine deaminase (ADA) and adenosine kinase (AK) activities. For uptake of purine nucleotides sequential action of ecto-5'-nucleotidase (ecto-5'-NT), nucleoside carrier and intracellular metabolism is necessary. Cells without ecto-5'-NT activity did not accumulate radioactivity from nucleotides. Proliferating neoplastic cells (K 562 and HL 60 cells) showed enhanced uptake of purine bases and nucleosides, when compared to quiescent cells (erythrocytes and granulocytes). From initial rates of uptake and intracellular enzyme activities it could be concluded that this enhanced uptake was due to alterations of enzyme pattern in the neoplastic cells.
...
PMID:Regulation of purine uptake in normal and neoplastic cells. 610 May 84

We propose that the ratio of [14C]formate-labelled purine nucleosides and bases (both intra and extracellular) to nucleic acid purines provides, in exponentially growing cultures, a sensitive index for comparative studies of purine metabolism. This ratio was 4-fold greater for an HGPRT- mutant than for the parental HGPRT+ human lymphoblast line. The major components of the labelled nucleoside and base fraction were hypoxanthine and inosine. By blocking adenosine deaminase activity with coformycin we found that approx. 90% of inosine was formed directly from IMP rather than the route IMP leads to AMP leads to adenosine leads to inosine. The ratio of labelled base + nucleosides to nucleic acids was essentially unchagned for an AK- lymphoblast line and 2-fold greater than control for an HGPRT(-)-KAK- line, demonstrating that a deficiency of adenosine kinase alone has little effect on the accumulation of purine nucleosides and bases. Although adenosine was a minor component of the nucleoside and base fraction, the adenosine fraction increased from 3 to 13% with the addition of coformycin to the HGPRT(-)-AK- line. In the parental and HGPRT- lines, adenosine was shown to be primarily phosphorylated rather than deaminated at concentrations less than 5 microM. Inhibition of IMP dehydrogenase activity by mycophenolic acid caused a 12- and 3-fold increase in the rate of production of labelled base and nucleoside in the parent and HGPRT- cells respectively. These results suggest that a mutationally induced partial deficiency in the activities converting IMP to guanine nucleotides may result in an increased catabolism of IMP.
...
PMID:Elucidation of aberrant purine metabolism: application to hypoxanthine-guanine phosphoribosylstransferase- and adenosine kinase-deficient mutants, and IMP dehydrogenase- and adenosine deaminase-inhibited human lymphoblasts. 610 30


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

---