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)

Some pyrimidine analogues--especially 6-azauridine and 5-azacytidine at a final concentration of 1 mmol dm-3--significantly depressed adenosine deaminase activity isolated and purified from bovine heart. Both the above mentioned azapyrimidine nucleosides were effective competitive inhibitors of this enzyme. The inhibitory effect of some clinically used pyrimidine analogues may be of importance for explanation of their mechanisms of action on the cell metabolism.
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PMID:Inhibition of bovine heart adenosine deaminase activity by some pyrimidine analogues. 683 35

The nucleoside antibiotic formycin, 7-amino-3-(beta-D-ribofuranosyl)pyrazolo(4,3-d)pyrimidine, a structural analogue of adenosine, is deaminated about 10-fold faster by adenosine deaminase than adenosine itself, and is therefore a superior substrate for both routine assays and kinetic studies with the purified enzyme. The luminescence properties of formycin have been profited from to develop a fluorimetric assay for adenosine deaminase which is considerably more sensitive than the spectrophotometric procedure widely employed with adenosine as substrate. Examples are presented of its application to routine assays of adenosine deaminase levels in cellular extracts, as well as to kinetic studies with the purified enzyme, including the properties of some pyrazolopyrimidine and purine substrates and inhibitors.
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PMID:Sensitive fluorimetric assay for adenosine deaminase with formycin as substrate; and substrate and inhibitor properties of some pyrazolopyrimidine and related analogues. 684 18

Canine cyclic hematopoiesis is an autosomal recessive disease characterized by regular 11-13-d cycles of the neutrophil, reticulocyte, and platelet counts caused by a defect in regulation of marrow stem cell proliferation. Treatment with lithium abrogates cycling of the cell counts in these grey collie dogs. Aware of the defective lymphopoiesis associated with adenosine deaminase and purine nucleoside phosphorylase deficiencies, we hypothesized that abnormal purine or pyrimidine metabolism might be present in these dogs. Using high pressure liquid chromatography, we measured erythrocyte purine and pyrimidine nucleotide levels and plasma purine and pyrimidine nucleosides and bases in normal and grey collie dogs before and during lithium treatment. During neutropenic periods in the grey collies, erythrocyte ATP, GTP, and UTP levels were significantly elevated. Normal dogs made neutropenic with cyclophosphamide did not show such elevations. Lithium treatment normalized the levels of erythrocyte ATP, GTP, and UTP in the grey collies and eliminated the differences between normal and grey collie nucleotide levels. Plasma thymine levels were markedly increased during neutropenia in the grey collie but were not increased in cyclophosphamide-treated normal dogs. The finding of abnormal concentrations of purine and pyrimidine metabolites in these dogs suggest that a metabolic derangement in purine or pyrimidine metabolism may be the cause of the defective stem cell proliferation in this disease.
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PMID:Canine cyclic hematopoiesis is associated with abnormal purine and pyrimidine metabolism. 685 18

Blockade of a metabolic pathway by interaction of a drug with a particular 'target enzyme' results in depletion of essential end-products of the pathway and accumulation of intermediates prior to the blockade. Metabolic resistance to a particular drug can arise if the substrate of the inhibited enzyme accumulates to levels sufficiently high to compete effectively with the inhibitor, leading to restoration of full activity of the metabolic pathway after a transitory delay. Such resistance has recently been demonstrated in vitro for the interaction of the tight-binding inhibitor N-phosphonacetyl-L-aspartate (PAcAsp) with the aspartate transcarbamoylase activity of the trifunctional protein which initiates pyrimidine biosynthesis in mammals [Christopherson, R. I. and Jones, M. E. (1980) J. Biol. Chem. 255, 11381-11395]. Carbamoyl phosphate, the product of the carbamoyl phosphate synthetase activity of this trifunctional protein, accumulates to a sufficiently high concentration that the inhibitory effect of PAcAsp is effectively abolished. We have developed a theoretical model for metabolic resistance which quantitatively accounts for these experimental data. This model has been used to simulate the interaction between the following potential or proven anti-cancer drugs and their target enzyme, under conditions similar to those which would occur in vivo: PAcAsp with aspartate transcarbamoylase; various OMP analogues [the 5'-monophosphates of 6-azauridine, pyrazofurin and 1-(beta-D-ribofuranosyl)-barbituric acid] with OMP decarboxylase; 5-fluorodeoxyUMP with thymidylate synthase; methotrexate with dihydrofolate reductase; and deoxycoformycin with adenosine deaminase.
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PMID:Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate. 687 66

Using 2'-deoxycoformycin inhibition of adenosine deaminase as a model of adenosine deaminase deficiency, the effects of 10 microM 2'-deoxyadenosine (dAdo) on the metabolism of concanavalin A (Con A)-stimulated rat thymocytes were studied. When dAdo and Con A were added simultaneously, a strong inhibition of the incorporation of [3H]thymidine (84%); [3H]uridine (98%) and L-[3H] leucine (46%) in the acid-insoluble fraction, and of [14C]formate (78%) and H14CO-3 (43%) uptake is observed after 48 h of incubation. When dAdo is added after 12 h of Con A stimulation, no such inhibition is observed, but when added after 24 h of stimulation, there is an enhancement of blastogenesis as measured by nucleic acid, protein, and purine and pyrimidine base synthesis. More detailed studies of thymocytes stimulated by Con A for 0-72 h, followed by short-term incubation periods with dAdo (1-5 h), revealed that thymocyte metabolism becomes progressively less sensitive to dAdo-mediated inhibition during the course of blastogenesis. These results suggest that (a) the inhibition of ribonucleotide reductase is not the only mechanism involved in the inhibition of blastogenesis by dAdo and that (b) such inhibition of thymocyte metabolism is essentially dependent upon the activation state of the cell.
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PMID:Consequences of adenosine deaminase deficiency on thymocyte metabolism. 697 17

A number of non-glycolytic metabolic abnormalities may occur in erythrocytes without significantly altering cell function or life span. They include deficiencies of adenine or hypoxanthine-guanine phosphoribosyltransferases, adenosine deaminase, nucleoside phosphorylase, and hyperactivity of ribosephosphate pyrophosphokinase. Three principal enzyme defects are causally associated with hemolytic anemia: hyperactive adenosine deaminase and deficiencies of adenylate kinase and pyrimidine nucleotidase. These produce hemolytic syndromes of variable severity ranging from mild or subclinical in the adenosine deaminase defect to severe in adenylate kinase deficiency. Pyrimidine nucleotidase deficiency is much more common and is associated with intermediate degrees of anemia. Acquired nucleotidase deficiency may occur secondary to lead toxicity and produces a syndrome virtually identical to the hereditary deficiency states.
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PMID:Hereditary disorders of erythrocyte enzymes in non-glycolytic metabolic pathways. 718 78

Hyperthermia specifically inhibits the repair of UV-induced DNA photolesions in transcriptionally active genes. To define more precisely which mechanisms underlie the heat-induced inhibition of repair of active genes, removal of cyclobutane pyrimidine dimers (CPDs) was studied in human fibroblasts with different repair capacities and different transcriptional status of the adenosine deaminase gene, i.e. normal human cells, human cells carrying an inactive copy of the adenosine deaminase gene and xeroderma pigmentosum complementation group C fibroblasts. The results indicate that repair of active genes is impaired by inhibition of two repair pathways: (i) a global repair system involved in the repair of CPDs in potentially active genes; and (ii) the transcription-coupled repair pathway responsible for the accelerated repair of the transcribed strand. Since X-ray-induced DNA damage is also preferentially removed from the transcribed strand of active genes, selective inhibition of repair of radiation-induced DNA damage in active genes may play a key role in radiosensitization due to hyperthermia.
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PMID:Selective inhibition of repair of active genes by hyperthermia is due to inhibition of global and transcription coupled repair pathways. 753 81

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

We investigated the contribution of the global and the transcription-coupled nucleotide excision repair pathway to the removal of structurally different DNA lesions. The repair kinetics of UV-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) were determined in an active and inactive gene in normal human fibroblasts and in xeroderma pigmentosum group C (XP-C) fibroblasts. Previously we have shown that in normal human cells exposed to a UV dose of 10 J/m2 repair of CPDs takes place via two pathways: global repair and transcription-coupled repair, the latter being responsible for accelerated repair of CPDs in the transcribed strand of active genes. So far, no clear evidence for transcription-coupled repair of 6-4PPs has been presented. Here we demonstrate that 6-4PPs really form a target for transcription-coupled repair. In XP-C cells, exposed to 30 J/m2 and only capable of performing transcription-coupled repair, CPDs as well as 6-4PPs are removed selectively and with similar kinetics from the transcribed strand of the adenosine deaminase (ADA) gene. The non-transcribed strand of the ADA gene and the inactive 754 gene are hardly repaired. In contrast to XP-C cells, normal cells exposed to 30 J/m2 lack strand-specific repair of both 6-4PPs and CPDs, suggesting that transcription-coupled repair is overruled by global repair, probably due to severe inhibition of transcription at this high UV dose. The much more rapid repair of 6-4PPs compared with CPDs in normal cells may be related to higher affinity of the global repair system for the former lesion. In XP-C cells the similarity of the rate of repair of both 6-4PPs and CPDs in the transcribed strand at 30 J/m2 indicates that transcription-coupled repair of photolesions takes place in a sequential way. Our results strongly suggest that the significance of transcription-coupled repair for removal of lesions depends on the type of lesion and on the dose employed.
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PMID:Transcription-coupled repair removes both cyclobutane pyrimidine dimers and 6-4 photoproducts with equal efficiency and in a sequential way from transcribed DNA in xeroderma pigmentosum group C fibroblasts. 783 46

Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imbalances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in purine metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nucleoside phosphorylase and adenosine monophosphate deaminase. In parallel, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-glial brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of purine metabolism in glial tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalances does not correspond to a simple gene dosage effect in these tumours. These data suggest that the decrease of adenosine metabolism occurs before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.
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PMID:Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations. 805 68


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