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:3.5.4.17 (adenosine deaminase)
5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine deaminase and adenosine kinase have been measured in rat liver, 12 transplantable hepatomas, regenerating, foetal and neonatal liver, adult and neonatal rat kidney and 2 transplantable kidney tumours. Adenosine, deaminase activity, relative to the normal liver value, was elevated 2-4 fold in hepatomas of rapid growth rate, was in the normal range in more slowly growing hepatomas and in regernerating liver, and was low in foetal and neonatal liver. Adenosine kinase activity was decreased, relative to rat liver values, in all the hepatomas; activity of this enzyme gave a negative correlation with tumour growth rate. Kinetic properties of the two enzymes were examined in partially purified preparations. Adenosine deaminases from both liver and rapidly growing hepatoma 3924A were subject to weak product inhibition by inosine. Adenosine kinase from liver and hepatoma 3924A was inhibited by the reaction products ADP and AMP, and the enzyme was also subject to excess substrate inhibition by concentrations of ATP in excess of 1 mM. In rat hepatoma cell lines growing in culture, the toxicity of adenosine correlated inversely with the ratio of adenosine deaminase activity to adenosine kinase activity. Chromatographic measurements showed that hepatoma cells incorporated less extracellular adenosine into their adenine nucleotide pools than did isolated liver cells. These results indicate that increased adenosine deaminase activity and decreased adenosine kinase activity may confer a selective advantage upon the cancer cell.
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PMID:Adenosine deaminase and adenosine kinase in rat hepatomas and kidney tumours. 20 96

We have previously reported the isolation and preliminary characterization of a mutant of Toxoplasma gondii that was resistant to adenine arabinoside. Fiftyfold higher concentrations of adenine arabinoside were required to inhibit the growth of the resistant parasite in human fibroblast cultures. To determine the enzymic basis for resistance, we measured the kinases and deaminases that act on adenosine or deoxyadenosine. All of these enzymic activities were found in uninfected human fibroblast cells. The mutant and wild type parasite proved to have similar activities of adenosine deaminase, deoxyadenosine deaminase, and deoxyadenosine kinase. However, the adenine arabinoside resistant mutant had less than 0.1% of the adenosine kinase activity observed in the wild type T. gondii. The mutant parasite is presumably resistant because without adenosine kinase to phosphorylate adenine arabinoside it cannot carry out the first step in the conversion of the analogue to adenine arabinoside triphosphate, the active form. A mutant of 3T6 (mouse) cells previously selected for a loss of adenosine kinase also proved to be resistant to adenine arabinoside.
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PMID:The biochemical basis for resistance to adenine arabinoside in a mutant of Toxoplasma gondii. 20 46

1. The maximal activities of 5'-nucleotidase, adenosine kinase and adenosine deaminase together with the Km values for their respective substrates were measured in muscle, nervous tissue and liver from a large range of animals to provide information on the mechanism of control of adenosine concentration in the tissues. 2. Detailed evidence that the methods used were optimal for the extraction and assay of these enzymes has been deposited as Supplementary Publication SUP 50088 (16pages) at the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K.,from whom copies can be obtained on the terms indicated in Biochem. J. (1978), 169, 5. This evidence includes the effects of pH and temperature on the activities of the enzymes. 3. In many tissues, the activities of 5'-nucleotidase were considerably higher than the sum of the activities of adenosine kinase and deaminase, which suggests that the activity of the nucleotidase must be markedly inhibited in vivo so that adenosine does not accumulate. In the tissues in which comparison is possible, the Km of the nucleotidase is higher than the AMP content of the tissue, and since some of the latter may be bound within the cell, the low concentration of substrate may, in part, be responsible for a low activity in vivo. 4. In most tissues and animals investigated, the values of the Km of adenosine kinase for adenosine are between one and two orders of magnitude lower than those for the deaminase. It is suggested that 5'-nucleotidase and adenosine kinase are simultaneously active so that a substrate cycle between AMP and adenosine is produced: the difference in Km values between kinase and deaminase indicates that, via the cycle, small changes in activity of kinase or nucleotidase produce large changes in adenosine concentration. 5. The activities of adenosine kinase or deaminase from vertebrate muscles are inversely correlated with the activities of phosphorylase in these muscles. Since the magnitude of the latter activities are indicative of the anaerobic nature of muscles, this negative correlation supports the hypothesis that an important role of adenosine is the regulation of blood flow in the aerobic muscles.
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PMID:Activities and some properties of 5'-nucleotidase, adenosine kinase and adenosine deaminase in tissues from vertebrates and invertebrates in relation to the control of the concentration and the physiological role of adenosine. 21 26

The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and adenosine. Although adenosine-induced pyrimidine starvation appears to contribute to this effect, uridine only partially reverses adenosine toxicity in WI-L2 and not at all in strain 107, an adenosine kinase-(ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) deficient derivative of WI-L2. Treatment of both cell lines with EHNA and adenosine leads to striking elevations in intracellular S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methylation reactions. The methylation in vivo of both DNA and RNA is inhibited by concentrations of EHNA and adenosine that elevate intracellular AdoHcy. Addition of 100 muM L-homocysteine thiolactone to cells treated with EHNA and adenosine enhances adenosine toxicity and further elevates AdoHcy to levels approximately 60-fold higher than those obtained in the absence of this amino acid, presumably by combining with adenosine to form AdoHcy in a reaction catalyzed by S-adenosylhomocysteine hydrolase (EC 3.3.1.1). In the adenosine kinase-deficient strain 107, a combination of ADA inhibition and L-homocysteine thiolactone markedly increases intracellular AdoHcy and inhibits growth even in the absence of exogenous adenosine. These results demonstrate a form of toxicity from endogenously produced adenosine and support the view that AdoHcy, by inhibiting methylation, is a mediator of uridine-resistant adenosine toxicity in these human lymphoblast lines. Furthermore, they suggest that AdoHcy may play a role in the pathogenesis of the severe combined immunodeficiency disease found in most children with heritable ADA deficiency.
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PMID:S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. 22 26

Metabolic studies in HEp-2/MP,MIR cells (an adenosine kinase, hypoxanthine phosphoribosyltransferase negative mutant) indicated the presence of adenosine phosphorylase activity. This activity, unknown in established mammalian cell lines, resulted in the glycosidic cleavage of both adenosine and the antiviral drug arabinosyladenine. The activity was observed readily in the presence or absence of the adenosine deaminase inhibitor conformycin. Isopycnic separation of [3H] thymidine-labeled DNA species in CsCl density gradients resulted in the appearance of two distinct peaks. The heavier peak coincided with [14C]thymidine-labeled marker DNA of human origin, whereas the lighter peak was within the range associated with mycoplasmal DNA. Testing by commercial laboratories confirmed the presence of mycoplasma in HEp-2/MP,MIR cells. The contaminant was identified as Mycoplasma hyorhinis, a porcine mycoplasma. Following gamma-irradiation (3000 rads) to block cellular mitosis, the mucoplasma-contaminated HEp-2/MP,MIR cells were cocultivated with mycoplasma-free wild-type HEp-2 cells which did not exhibit adenosine phosphorylase activity. Following serial cocultivation in a medium designed to favor the survival of the wild-type cells, adenosine phosphorylase activity was found in the previously uninfected cells. Studies of this nature emphasize the need for investigators to carefully monitor their cell lines for mycoplasma.
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PMID:Adenosine phosphorylase activity in a mutant HEp-2 cell line contaminated with Mycoplasm hyorhinis. 40 62

The metabolism of the methylase product inhibitor S-adenosylhomocysteine and its 7-deaza analogue S-tubercidinylhomocysteine has been studied in cultured N-18 neuroblastoma cells. The latter compound, designed to resist metabolic degradation, has been shown to be inert under the same conditions where S-adenosylhomocysteine is rapidly and extensively degraded. The product analyses elucidated by high-performance liquid chromatography indicate that the primary route of S-[8-(14)C]adenosylhomocysteine metabolism in these cells leads to adenosine. This product does not accumulate but is rapidly converted to nucleotides or oxypurines by the action of adenosine kinase and adenosine deaminase, respectively. The presence of the potent adenosine deaminase inhibitor coformycin leads to a pronounced inhibition of oxypurine formation, an increase in nucleotide formation, and a slight accumulation of the primary metabolic products adenosine and adenine.
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PMID:Metabolism of S-adenosylhomocysteine and S-tubercidinylhomocysteine in neuroblastoma cells. 44 79

Adenine nucleotide breakdown to nucleosides and purine bases was measured in cultures of human lymphoblastoid cells following: 1) the inhibition of oxidative phosphorylation in the absence of glucose or 2) the addition of 2-deoxyglucose. A mutant cell line, deficient in adenosine kinase, in the presence of an adenosine deaminase inhibitor was used to measure utilization of the two pathways of AMP catabolism involving initial action of either purine 5'-nucleotidase or AMP deaminase. In such a system the appearance of adenosine induced by the oxidative phosphorylation inhibitor, rotenone, implies that approximately 70% of AMP breakdown occurs via dephosphorylation. By the same method, deamination accounts for 82% of AMP breakdown when 2-deoxyglucose is added. The occurrence of AMP dephosphorylation is not correlated with elevated concentrations of substrate or with decreased concentrations of the inhibitors of 5'-nucleotidase, ATP and ADP. Dephosphorylation occurs if, and only if, the adenylate energy charge decreases to about 0.6 in these experiments. In cultures deprived of glucose and oxygen, adenine nucleotide degradation via dephosphorylation results in recovery of normal energy charge values.
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PMID:Adenine nucleotide degradation during energy depletion in human lymphoblasts. Adenosine accumulation and adenylate energy charge correlation. 47 72

Changes in hepatic purine enzyme activities of chicks fed diets containing 11%, 20%, 43% and 80% protein were correlated with protein intake and uric acid production in order to identify those enzymes with activities that parallel closely and may regulate uric acid production. Nucleoside phosphorylase, xanthine dehydrogenase, adenylosuccinate synthetase and adenosine kinase correlated positively with protein intake and uric acid production. Adenosine deaminase, 5'-nucleotidase (AMP), adenylate deaminase and adenine phosphoribosyltransferase correlated negatively with protein intake and uric acid production. Hypoxanthine phosphoribosyltransferase and 5'-nucleotidase (IMP) were unaffected by protein intake and did not correlate with uric acid production. The ratio of adenosine kinase to adenosine deaminase correlated positively with protein intake and uric acid production. The increased activities of adenylosuccinate synthetase and adenosine kinase, along with the reduced activities of 5'-nucleotidase and adenylate deaminase, in liver from chickens fed the 80% compared with the 11% protein diet demonstrate enhanced synthesis of adenine nucleotides. Since adenine nucleotides are essential cofactors for de novo purine synthesis, it is proposed that adenylosuccinate synthetase, adenosine kinase, 5'-nucleotidase and adenylate deaminase are key enzymes involved in the regulation of purine biosynthesis.
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PMID:Protein intake, hepatic purine enzyme levels and uric acid production in growing chicks. 61 42

The metabolic and growth inhibitory effects of adenosine toward the human lymphoblast line WI-L2 were potentiated by the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and coformycin. EHNA, 5 micron, or coformycin, 3.5 micron, at concentrations that inhibited adenosine deaminase activity more than 90% had little effect on cell growth or the metabolic parameters studied. Adenosine, 50 micron, plus EHNA, 5 micron, arrested cell growth in both parent and adenosine kinase-deficient lymphoblasts, implicating the nucleoside as the mediator of the cytostatic effect. Adenosine, 50 micron, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90%, and reduced pyrimidine ribonucleotide concentrations. Uridine, 10 or 100 micron, reversed adenosine plus EHNA growth inhibition in WI-L2 but not in adenosine kinase mutants. Adenine, 500 micron, which may be converted to the same intracellular nucleotides as adenosine, reduced the growth rate by 50% in both parent and adenine phosphoribosyltransferase-deficient lymphoblasts. Although adenine also depleted cells of 5-phosphoribosyl-1-pyrophosphate and reduced pyrimidine ribonucleotide by 50%, the mechanisms of adenine and adenosine toxicity differ. In contrast to the ability of uridine to reverse adenosine cytostasis, growth inhibition by adenine was not reversed by uridine, indicating that pyrimidine ribonucleotide depletion is not the primary mechanisms of adenine toxicity.
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PMID:Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts. 66 33

Clonal lines, with either partial or total deficiency of adenine phosphoribosyltransferase (APRT) were derived from the WI-L2 long-term human lymphocyte line by selection for resistance to the adenine analogs 8-azaadenine or 2,6-diaminopurine. Resistance to 8-azaadenine also conferred resistance to 2,6 diaminopurine and vice versa. Cells with 30--40% of wild-type APRT activity were selected by resistance to 0.01 mM 2,6-diaminopurine or 1.40 mM 8-azaadenine. The APRT in the 8-azaadinine-resistant cells exhibited a four- to sevenfold increase in the apparent Km for adenine. Activities of three other purine reutilization and interconversion enzymes in the resistant cells, including hypoxanthine phosphoribosyltransferase (HPRT), adenosine kinase, and adenosine deaminase, were within the range of wild-type activities. The doubling times of the APRT-deficient cells in purine-free medium was not different from wild-type cells. The APRT in the 8-azaadenine-resistant cells did not have an altered mobility in glycerol gradients as compared to wild-type cells. The rate of purine synthesis de novo and intracellular levels of 5-phosphoribosyl-1-pyrophosphate were unchanged in the APRT-deficient cells as compared to WI-L2. The ability of the cells to reutilize exogenous adenine, however, was severely impaired.
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PMID:Purine reutilization and synthesis de novo in long-term human lymphocyte cell lines deficient in adenine phosphoribosyltransferase activity. 69 20


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