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 catabolism of purine nucleotides was investigated by both chemical and radiochemical methods in isolated rat hepatocytes, previously incubated with [(14)C]adenine. The production of allantoin reached 32+/-5nmol/min per g of cells (mean+/-s.e.m.) and as much as 30% of the radioactivity incorporated in the adenine nucleotides was lost after 1h. This rate of degradation is severalfold in excess over values previously reported to occur in the liver in vivo. An explanation for this enhancement of catabolism may be the decrease in the concentration of GTP. 2. In a high-speed supernatant of rat liver, adenosine deaminase was maximally inhibited by 0.1mum-coformycin. The activity of AMP deaminase, measured in the presence of its stimulator ATP in the same preparation, as well as the activity of the partially purified enzyme, measured after addition of its physiological inhibitors GTP and Pi, required 50mum-coformycin for maximal inhibition. 3. The production of allantoin by isolated hepatocytes was not influenced by the addition of 0.1mum-coformycin, but was decreased by concentrations of coformycin that were inhibitory for AMP deaminase. With 50mum-coformycin the production of allantoin was decreased by 85% and the formation of radioactive allantoin from [(14)C]adenine nucleotides was completely suppressed. 4. In the presence of 0.1mum-coformycin or in its absence, the addition of fructose (1mg/ml) to the incubation medium caused a rapid degradation of ATP, without equivalent increase in ADP and AMP, followed by transient increases in IMP and in the rate of production of allantoin; adenosine was not detectable. In the presence of 50mum-coformycin, the fructose-induced breakdown of ATP was not modified, but the depletion of the adenine nucleotide pool proceeded much more slowly and the rate of production of allantoin increased only slightly. No rise in IMP concentration could be detected, but AMP increased manyfold and reached values at which a participation of soluble 5'-nucleotidase in the catabolism of adenine nucleotides is most likely. 5. These results are in agreement with the hypothesis that the formation of allantoin is controlled by AMP deaminase. They constitute further evidence that 5'-nucleotidase is inactive on AMP, unless the concentration of this nucleotide rises to unphysiological values.
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PMID:Purine catabolism in isolated rat hepatocytes. Influence of coformycin. 747 45

Pathways producing and converting adenosine have hardly been investigated in human heart, contrasting work in other species. We compared the kinetics of enzymes associated with purine degradation and salvage in human and rat heart cytoplasm assaying for adenosine deaminase, nucleoside phosphorylase, xanthine oxidoreductase, AMP deaminase, AMP- and IMP-specific 5'-nucleotidases, adenosine kinase and hypoxanthine guanine phosphoribosyltransferase (HGPRT). Xanthine oxidoreductase was not detectable in human heart. The Km-values of the AMP-catabolizing enzymes were 2-5 times higher in human heart; the substrate affinity of the other enzymes was in the same order of magnitude in both species. The maximal activity (Vmax) of adenosine kinase was the same in both species, but HGPRT in man was only 12% of that in the rat. For human heart the Vmax-values of adenosine deaminase, nucleoside phosphorylase, AMP- and IMP-specific 5'-nucleotidases, and AMP deaminase were 25-50% of those for rat heart. We conclude that human heart is less geared to purine catabolism than rat heart as is evident from the lower activities of the catabolic enzymes. Maintenance of the nucleotide pool may thus play a more important role in human heart.
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PMID:Kinetics of adenylate metabolism in human and rat myocardium. 759 55

AMP deaminase (AMPD) catalyzes the hydrolytic deamination of AMP to IMP and NH3. This activity is represented throughout mammalian tissues and cells by at least three isoforms. Human AMPD cDNAs have been cloned and sequenced, leading to predictions that each isoform contains distinct amino-ends (N-terminal regions) in contrast to their highly conserved carboxyl-ends (C-terminal regions). Wild type, truncated, and chimeric human AMPD1 (isoform M) and AMPD2 (isoform L) cDNAs were expressed and the resultant activities partially characterized as a means to examine the role of divergent N-terminal regions in these polypeptides (residues 1-262 and 1-258 of isoforms M and L, respectively) on isoform-specific catalytic properties. Similar to activities purified from human tissues, in the presence of monovalent cation, wild type isoform M displayed hyperbolic kinetics in the presence and absence of ATP, whereas wild type isoform L exhibited allosteric activation in the presence of this nucleotide effector. Expression of both a chimeric M (5'-AMPD1)/L (3'-AMPD2) construct and one in which the N-terminal region of isoform L was deleted produced activities that were also allosterically regulated by ATP. However, no AMPD activity was detectable following expression of either a chimeric L (5'-AMPD2)/M (3'-AMPD1) construct or one in which the N-terminal region of isoform M had been deleted. The N-terminal region also affected the relative ability of each recombinant AMPD activity to deaminate substrate analogs modified in either the sugar or the phosphate, but not in the purine base, moieties of AMP. These combined data show (i) that isoform M, but not isoform L, absolutely requires its N-terminal region for proper function, (ii) that the C-terminal region of isoform L is responsible for allosteric activation by ATP, (iii) an effect of the N-terminal region on substrate-enzyme interaction, a contention that is discussed in context with available information regarding the related purine catabolic activity, adenosine deaminase.
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PMID:Divergent N-terminal regions in AMP deaminase and isoform-specific catalytic properties of the enzyme. 764 62

A large series of samples obtained after surgical resection of intestinal mucosa of patients affected by intestinal carcinoma was examined in order to define possible relationships between levels of enzymes involved in the purine salvage pathway and clinical/biological parameters of aggressiveness and invasiveness. The results confirm our previous observation on a different pattern of purine salvage enzymes in tumor as compared to normal colon tissues (Camici et al., 1990). In fact, we observed in human colon tumor tissues a significant enhancement of the three enzymes involved in the synthesis of IMP, hypoxanthine guanine phosphoribosyltransferase (HGPRT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). On the other hand, no variation was observed in the 5'-nucleotidase and alkaline phosphatase activities. While we could not find a significant correlation between HGPRT, ADA and PNP activities and histologic grading or biological parameters of tumor aggressiveness, the significant correlation with the extent of disease, as expressed by the Dukes' stage, would demonstrate at least for human colon tumors, a relationship between enzyme activity and tumor invasiveness.
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PMID:Relationship between the levels of purine salvage pathway enzymes and clinical/biological aggressiveness of human colon carcinoma. 779 89

Evaluation of enzyme activities involved in nucleotide metabolism and adenosine production within different cell types can provide important information on their contribution to the overall metabolism of the heart. The following enzyme activities were determined: adenosine kinase (AK), adenosine deaminase (ADA), S-adenosylhomocysteine hydrolase (SAHH), purine nucleoside phosphorylase (PNP), AMP deaminase (AMPD), membrane 5'nucleotidase (M5'N), AMP specific (AC5'N) and IMP specific (IC5'N) cytosolic 5'nucleotidases in (1) rat heart (n = 5), (2) rat cardiomyocytes obtained by collagenase digestion (n = 5), (3) human heart (n = 6) obtained from explants or papillary muscles collected during heart transplantation or mitral valve replacement, and (4) human umbilical cord endothelial cells in primary culture (n = 4). In the human heart, activities (mumol/min/g wet weight) were as follows: AK (0.14 +/- 0.01), ADA (0.46 +/- 0.03), SAHH (0.001 +/- 0.0003), PNP (0.43 +/- 0.08), AMPD (0.41 +/- 0.05), M5'N (1.75 +/- 0.12), IC5'N (0.21 +/- 0.03) and AC5'N (0.11 +/- 0.02). These enzyme activities were lower than those determined in the rat heart with the exception of AC5'N and IC5'N which were equal. The most prominent difference observed was for AMPD and M5'N which were nine and five-fold more active in the rat heart. Rat cardiomyocyte enzyme activities were comparable to those measured in whole rat heart with the exception of ADA (six-fold lower) and PNP (16-fold lower). Endothelial cell activities were notably different from those in the human heart particularly in the case of SAHH (nine-fold higher) and PNP (16-fold higher).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleotide and adenosine metabolism in different cell types of human and rat heart. 789 72

Exogenous adenosine triphosphate (ATP) added to brush-border membrane vesicles was rapidly degraded mainly to inosine according to the high ecto-nucleotidase activities in these vesicles. In the absence of phosphate, inosine was slowly transformed into hypoxanthine, and xanthine oxidase and dehydrogenase activities were not detected. The presence of ecto-adenosine deaminase and ecto-adenosine monophosphate (AMP) nucleotidase was shown. The ecto-adenosine deaminase was inhibited by deoxycoformycin and was also detected in rat renal brush-border membrane vesicles. Using orthovanadate, levamisole, and alpha, beta-methylene adenosine diphosphate as possible inhibitors, alkaline phosphatase was shown to be the main agent responsible for ecto-AMP nucleotidase activity. In pig renal basolateral membrane vesicles and in whole cell extracts from pig renal cortex, ecto-AMP nucleotidase was the limiting factor in ATP degradation. Comparing the ATP catabolism in the whole cell cortical extract with the catabolism in the same sample precleared of membranes, it was shown that ectonucleotidase activity is mainly bound to the membranous components. It is also shown that the whole cell extract of pig renal cortex has hypoxanthine phosphoribosyl transferase activity, and it seems probable that the rapid and specific formation of luminal inosine and its transport into the cell in competition with adenosine may start the purine salvage pathway through the synthesis of IMP from hypoxanthine.
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PMID:Adenine nucleotides and adenosine metabolism in pig kidney proximal tubule membranes. 840 44

2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno) are potent and selective inhibitors of the replication of the human immunodeficiency virus type 1 (HIV1) in several cell culture systems. Equipotent in terms of antiviral activity, both compounds selectively inhibit the reverse transcription of HIV-1 by virtue of their conversion into ddATP. In human lymphoid cells ddAdo is converted to the active metabolite, ddATP, but it also undergoes rapid deamination, via adenosine deaminase, to form ddIno. ddIno, like ddAdo, gives rise to dideoxynucleotides of the dideoxy-adenylate series (ddAMP, ddADP and ddATP), as well as to IMP and to adenylate ribonucleotides. With the main object of blocking the deamination of ddAdo, we studied its anti-HIV-1 activity in the presence of different adenosine deaminase inhibitors, namely Coformycin (CF), 9-(erythro-2-hydroxy-3-nonyl) adenine (EHNA) and some deaza-EHNA derivatives. In contrast with reports on 2'-deoxycoformycin (Cooney et al., 1987), the adenosine deaminase inhibitors tested by us showed a significant increase in the antiviral activity of ddAdo, but not of ddIno. Enhancement was obtained with EHNA and CF concentrations up to 250 and > 12,500 times lower than their respective maximum non toxic doses. In combination with EHNA or CF, ddAdo could be used at concentrations up to ten times lower than those required to obtain the same degree of inhibition when ddAdo (or ddIno) was used alone. The use of EHNA or CF in combination with ddAdo at concentrations that inhibit the multiplication of HIV-1, allowed uninfected cells to maintain their normal multiplication rates. In fact, in combination experiments, cytotoxic effects were evident only with doses of EHNA, or CF and ddAdo 10 to 100 or more times higher than those required to inhibit HIV-1 significantly. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
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PMID:Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives. 859 Mar 88

Human lymphocytes lacking adenosine deaminase die and T-cell leukemias are killed by deoxycoformycin (dCf), an inhibitor of adenosine deaminase, due to impaired metabolism of dAdo. The initial metabolism of exogenous adenosine (Ado) and deoxyadenosine (dAdo) has been compared in human erythrocytes and CCRF-CEM leukemia cells and the data obtained have been simulated using kinetic constants obtained in vitro for the enzymes involved. Cells were mixed with 3H-labelled Ado and dAdo, samples were taken at 3 sec intervals and progress curves for the 3H-labelled metabolites formed were determined by quantitative two-dimensional thin layer chromatography. Erythrocytes rapidly take up Ado and the predominant metabolite after 60 sec is hypoxanthine (Hyp), while for dAdo, deoxyinosine (dIno) predominates. By contrast, leukemia cells convert to Ado predominantly to AMP, while dAdo is converted first to Hyp and the to AMP. The presence of dCf had little effect upon Ado metabolism by induced accumulation of dAdo. Erythrocytes rapidly degrade Ado and dAdo to Hyp, although the phosphorolysis of dIno is relatively slow. Human CCRF-CEM leukemia cells convert most of the Ado or dAdo to AMP after 60 sec. For dAdo, the sequence of reactions would be dAdo-->dIno-->Hyp-->IMP-->sAMP-->AMP. dCf does not significantly affect the conversion of Ado-->AMP, but dCf blocks AMP accumulation from dAdo, consistent with the reaction sequence shown above. A computer model has been developed for the metabolism of Ado and dAdo, but some of the kinetic constants determined in vitro for this model do not pertain to intact cells.
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PMID:Metabolism of adenosine and deoxyadenosine by human erythrocytes and CCRF-CEM leukemia cells. 902 97

The pool of free purine derivatives and activities of the key enzymes of purine metabolism (adenosine deaminase, purine nucleoside phosphorylase, and 5'-nucleotidase) in lymphocytes, erythrocytes, and epidermis homogenates were measured in 20 normal subjects and 15 patients with psoriasis by high-performance liquid chromatography. The levels of AMP, GMP, and IMP purine monophosphates are decreased in the epidermis and red cells of psoriasis patients, whereas the final products of hypoxanthine, xanthine, and uric acid metabolism are accumulating, and the activities of ADA and PNP are increased double in the skin, all this indicating purine derivatives catabolism.
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PMID:[Metabolism of purine compounds in psoriasis]. 957 24

Adenosine, through activation of membrane-bound receptors, has been reported to have neuroprotective properties during strokes or seizures. The role of astrocytes in regulating brain interstitial adenosine levels has not been clearly defined. We have determined the nucleoside transporters present in rat C6 glioma cells. RT-PCR analysis, (3)H-nucleoside uptake experiments, and [(3)H]nitrobenzylthioinosine ([(3)H]NBMPR) binding assays indicated that the primary functional nucleoside transporter in C6 cells was rENT2, an equilibrative nucleoside transporter (ENT) that is relatively insensitive to inhibition by NBMPR. [(3)H]Formycin B, a poorly metabolized nucleoside analogue, was used to investigate nucleoside release processes, and rENT2 transporters mediated [(3)H]formycin B release from these cells. Adenosine release was investigated by first loading cells with [(3)H]adenine to label adenine nucleotide pools. Tritium release was initiated by inhibiting glycolytic and oxidative ATP generation and thus depleting ATP levels. Our results indicate that during ATP-depleting conditions, AMP catabolism progressed via the reactions AMP --> IMP --> inosine --> hypoxanthine, which accounted for >90% of the evoked tritium release. It was surprising that adenosine was not released during ATP-depleting conditions unless AMP deaminase and adenosine deaminase were inhibited. Inosine release was enhanced by inhibition of purine nucleoside phosphorylase; ENT2 transporters mediated the release of adenosine or inosine. However, inhibition of AMP deaminase/adenosine deaminase or purine nucleoside phosphorylase during ATP depletion produced release of adenosine or inosine, respectively, via the rENT2 transporter. This indicates that C6 glioma cells possess primarily rENT2 nucleoside transporters that function in adenosine uptake but that intracellular metabolism prevents the release of adenosine from these cells even during ATP-depleting conditions.
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PMID:Purine uptake and release in rat C6 glioma cells: nucleoside transport and purine metabolism under ATP-depleting conditions. 1098 33


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