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 effects of ribonucleotide reductase inhibitors on the growth of the human colon carcinoma cell line HT-29 were examined. Inhibitors were chosen for these studies that were specifically directed at each of the subunits of ribonucleotide reductase. The concentrations of drugs required to inhibit the growth of HT-29 cells by 50% (IC50) for hydroxyurea, 2,3-dihydro-lH-pyrazole-[2,3a]imidazole (IMPY), and 4-methyl-5-amino-l-formyl-isoquinoline thiosemicarbazone (MAIQ) were 206, 996, and 3.2 microM, respectively. Although the IC50 for deoxyadenosine alone was greater than 2,000 microM, in the presence of 5 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), which protects deoxyadenosine from deamination by adenosine deaminase, it was reduced to 112 microM. The IC50 for deoxyguanosine was 1,060 microM. The addition of 8-aminoguanosine to protect deoxyguanosine from phosphorolysis by purine nucleoside phosphorylase did not increase the toxicity of deoxyguanosine in HT-29 cells. The combination of MAIQ or IMPY and deoxyadenosine/EHNA gave strong synergistic inhibition of HT-29 cell growth. The results of these studies indicate that ribonucleotide reductase inhibitors effectively block the growth of human colon carcinoma HT-29 cells and that combinations of inhibitors directed at the individual subunits of reductase result in synergistic inhibition of HT-29 cell growth in culture.
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PMID:Effect of ribonucleotide reductase inhibitors on the growth of human colon carcinoma HT-29 cells in culture. 220 72

A sample of children treated by phototherapy during the neonatal period has been studied in the population of Penne (South Eastern Italy) in order to confirm the association previously reported in newborns from the population of Rome between neonatal jaundice and phenotypes of adenosine deaminase (ADA) and acid phosphatase (ACP1). The present data confirm that the incidence of clinically relevant jaundice is much greater in newborns of phenotype ACP1 BA carrying ADA2 allele than in other infants. Since ACP1 probably acts as flavin mononucleotide phosphatase and is modulated by purine nucleotides, it is likely that enzymes of purine nucleotide metabolism (including ADA), ACP1 and flavoenzymes (including gluthatione reductase and enzymes of Krebs cycle), may represent a polygenic complex influencing bilirubin levels in the first few days of life.
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PMID:Enzyme variability and neonatal jaundice. The role of adenosine deaminase and acid phosphatase. 281 3

The number of gene assignments to human chromosome 20 has increased slowly until recently. Only seven genes and one fragile site were confirmed assignments to chromosome 20 at the Ninth Human Gene Mapping Workshop in September 1987 (HGM9). One fragile site, 13 additional genes, and 10 DNA sequences that identify restriction fragment length polymorphisms (RFLPs), however, were provisionally added to the map at HGM9. Five mutated genes on chromosome 20 have a relation to disease: a mutation in the adenosine deaminase gene results in a deficiency of the enzyme and severe combined immune deficiency; mutations in the gene for the growth hormone releasing factor result in some forms of dwarfism; mutations in the closely linked genes for the hormones arginine vasopressin and oxytocin and their neurophysins are probably responsible for some diabetes insipidus; and mutations in the gene that regulates both alpha-neuraminidase and beta-galactosidase activities determine galactosialidosis. The gene for the prion protein is on chromosome 20; it is related to the infectious agent of kuru, Creutzfeld-Jacob disease, and Gertsmann-Straussler syndrome, although the nature of the relationship is not completely understood. Two genes that code for tyrosine kinases are on the chromosome, SRC1 the proto-oncogene and a gene (HCK) coding for haemopoietic kinase (an src-like kinase), but no direct relation to cancer has been shown for either of these kinases. The significance of non-random loss of chromosome 20 in the malignant diseases non-lymphocytic leukaemia and polycythaemia vera is not understood. Twenty-four additional loci are assigned to the chromosome: five genes that code for binding proteins, one for a light chain of ferritin, genes for three enzymes (inosine triphosphatase, s-adenosylhomocysteine hydrolase, and sterol delta 24-reductase), one for each of a secretory protein and an opiate neuropeptide, a cell surface antigen, two fragile sites, and 10 DNA sequences (one satellite and nine unique) that detect RFLPs.
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PMID:The map of chromosome 20. 307 44

The simultaneous administration of 3'-deoxyadenosine N1-oxide (3'-dANO) and the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) or 2'-deoxycoformycin (2'-dCF) to mice bearing Ehrlich ascites tumor cells resistant to 3'-dANO resulted in 80%-90% inhibition of tumor growth in vivo. 3'-dANO and 2'-dCF increased the survival time of tumor-bearing mice by a factor of 2. In vitro studies showed that the 3'-dANO resistant Ehrlich cells initiate the metabolism of 3'-dANO by a reduction to 3'-deoxyadenosine, which is converted primarily to 3'-deoxyinosine by adenosine deaminase and, to a small extent, phosphorylated to the cell toxic agent 3'-dATP. By the addition of EHNA or 2'-dCF it was possible to block the formation of 3'-deoxyinosine, resulting in a profound stimulation in the accumulation of 3'-dATP. The development of resistance to 3'-dANO was studied in cell cultures and found to be accompanied by changes in the enzyme activities of the reductase, the adenosine kinase, and the adenosine deaminase.
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PMID:Synergistic effect of 3'-deoxyadenosine N1-oxide and adenosine deaminase inhibitors on growth of Ehrlich ascites tumor cells in vivo. 325 21

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.
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PMID:Studies on the mechanism of cytotoxicity of 3'-deoxyadenosine N1-oxide in different strains of Ehrlich ascites tumor cells. 349 46

We sought to define the cellular activity that mediates resistance in human leukemic cells (CCRF-CEM) to the nucleoside 9-beta-D-arabinofuranosyladenine (ara-A). Stable mutants were obtained by continuous selection at ara-A concentrations of 1 or 2.5 microM in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin. Four clones selected for further investigation were 4- to 11-fold less sensitive to the cytotoxicity of ara-A than the parental CCRF-CEM line. These clones also showed cross-resistance to deoxyadenosine and thymidine, but normal sensitivity to arabinosylcytosine and adenosine, and increased sensitivity to the etoposide VP16-213. No change was found in the activity of kinases that phosphorylate ara-A and the various nucleosides that could account for the resistant phenotype in these mutant lines. Resistance was associated with a 2- to 8-fold increase in the level of all four deoxyribonucleoside triphosphates. The triphosphate pools in the mutants were resistant to the inhibition produced in wild-type cells by addition of deoxy-adenosine or thymidine, although significant activation in the deoxyguanosine triphosphate pool was obtained by higher concentrations of thymidine. An examination of ribonucleotide reductase in extracts of two of the mutants revealed a specific alteration in the normal sensitivity of the enzyme for deoxyadenosine triphosphate and adenosine triphosphate but not 9-beta-D-arabinofuranosyladenine 5'-triphosphate. When the level of ribonucleotide reductase activity was measured, it was found that the ara-A-resistant cells contained approximately twice the wild-type level of cytidine diphosphate reductase activity at physiological adenosine triphosphate level. This combination of increased enzyme activity and alteration in sensitivity to the nucleoside triphosphates could account for both the changes in deoxyribonucleotide pool sizes and the resistant phenotype of the presumed mutants.
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PMID:Selection of 9-beta-D-arabinofuranosyladenine-resistant human T-lymphoblasts with altered ribonucleotide reductase activity. 638 Jul 7

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

Adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4)-deficient patients recently were found to have abnormally high levels of dATP, a negative allosteric effector of ribonucleotide reductase (ribonucleoside-diphosphate reductase, 2'-deoxyribonucleoside-diphosphate:oxidized thioredoxin 2'-oxidoreductase, EC 1.17.4.1). Therefore it was proposed that the immunodeficiency associated with adenosine deaminase deficiency is mediated through inhibition of ribonucleotide reductase and hence DNA replication. HeLa cells, treated with an adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine, and deoxyadenosine to mimic the adenosine deaminase-deficient state, were monitored to determine directly the effects on ribonucleotide reductase activity and levels. A low concentration of erythro-9-(2-hydroxy-3-nonyl)adenine, which did not inhibit cell growth, nevertheless retarded the cells in G2 + M phase of the cell cycle and increased reductase activity. Reductase activity was also elevated in cells treated with a low level of deoxyadenosine which did not affect the cell cycle or cell growth. However, ribonucleotide reductase activity was reduced to one-half of the control value in cells treated with either enough deoxyadenosine to inhibit cell growth or with a combination of erythro-9(2-hydroxy-3-nonyl)adenine and deoxyadenosine, each at concentrations which individually do not inhibit cell growth. Removal of deoxynucleotides, particularly dATP, from these extracts increased ribonucleotide reductase activity to several-fold higher than control values. The reduced activity of ribonucleotide reductase in the simulated adenosine deaminase-deficient HeLa cells provides direct evidence for the thesis that adenosine deaminase deficiency disease is mediated through elevated levels of dATP which inhibit ribonucleotide reductase. In addition, the cell cycle patterns and ribonucleotide reductase levels suggest that the regulatory substance(s) that controls the level of ribonucleotide reductase is not operative until the late S or G2 phase of the cell cycle.
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PMID:Adenosine deaminase impairment and ribonucleotide reductase activity and levels in HeLa cells. 699 99

In an effort to improve the pharmacokinetic properties and tissue distribution of 2'-F-ara-ddI, two lipophilic prodrugs, 6-azido-2'-3'-dideoxy-2'-fluoro-beta-D- arabinofuranosylpurine (FAAddP, 4) and N6-methyl-2'-3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine (FMAddA, 5), were synthesized and their biotransformation was investigated in vitro and in vivo, in mice. Compounds 4 and 5 were synthesized via the intermediate 2. For the in vitro studies, FAAddP and FMAddA were incubated in mouse serum, liver homogenate, and brain homogenate. FAAddP was metabolized in liver homogenate by the reduction of the azido to the amino moiety followed by deamination, yielding 2'-F-ara-ddI. The conversion of FAAddP to 2'-F-ara-ddA was mediated by microsomal P-450 NADPH reductase system, as shown by the liver microsomal assay. FAAddP was also converted to 2'-F-ara-ddI at a slower rate in the brain than in the liver. FMAddA, however, was stable in brain homogenate and was slowly metabolized in the liver homogenate. Metabolic conversion of FMAddA in vitro was stimulated by the addition of adenosine deaminase. In the in vivo metabolism study, FAAddP underwent reduction to 2'-F-ara-ddA followed by deamination to 2'-F-ara-ddI. FMAddA did not result in increased brain delivery of 2'-F-ara-ddI in vivo, probably due to the slow conversion as observed in the in vitro studies. However, there was an increase in the half-life of 2'-F-ara-ddI produced from FMAddA. This report is the first example in the design of prodrugs using the azido group for adenine- and hypoxanthine-containing nucleosides. This interesting and novel approach can be extended to other antiviral and anticancer nucleosides.
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PMID:In vitro and in vivo evaluation of 6-azido-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosylpurine and N6-methyl-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine as prodrugs of the anti-HIV nucleosides 2'-F-ara-ddA and 2'-F-ara-ddI. 891 56

To examine the role of AMP-activated protein kinase (AMPK; EC 2.7.1. 109) in the regulation of autophagy, rat hepatocytes were incubated with the AMPK proactivators, adenosine, 5-amino-4-imidazole carboxamide riboside (AICAR), or N6-mercaptopurine riboside. Autophagic activity was inhibited by all three nucleosides, AICAR and N6-mercaptopurine riboside being more potent (IC50 = 0.3 mM) than adenosine (IC50 = 1 mM). 2'-Deoxycoformycin, an adenosine deaminase (EC 3.5.4.4) inhibitor, increased the potency of adenosine 5-fold, suggesting that the effectiveness of adenosine as an autophagy inhibitor was curtailed by its intracellular deamination. 5-Iodotubercidin, an adenosine kinase (EC 2.7.1.20) inhibitor, abolished the effects of all three nucleosides, indicating that they needed to be phosphorylated to inhibit autophagy. A 5-iodotubercidin-suppressible phosphorylation of AICAR to 5-aminoimidazole-4-carboxamide riboside monophosphate was confirmed by chromatographic analysis. AICAR, up to 0.4 mM, had no significant effect on intracellular ATP concentrations. Because activated AMPK phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88), the rate-limiting enzyme in cholesterol synthesis, the strong inhibition of hepatocytic cholesterol synthesis by all three nucleosides confirmed their ability to activate AMPK under the conditions used. Lovastatin and simvastatin, inhibitors of HMG-CoA reductase, strongly suppressed cholesterol synthesis while having no effect on autophagic activity, suggesting that AMPK inhibits autophagy independently of its effects on HMG-CoA reductase and cholesterol metabolism.
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PMID:Inhibition of hepatocytic autophagy by adenosine, aminoimidazole-4-carboxamide riboside, and N6-mercaptopurine riboside. Evidence for involvement of amp-activated protein kinase. 972 84


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