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)

Intracellular adenosine formation and release to extracellular space was studied in WI-L2-B and SupT1-T lymphoblasts under conditions which induce or do not induce ATP catabolism. Under induced conditions, B lymphoblasts but not T lymphoblasts, release significant amounts of adenosine, which are markedly elevated by adenosine deaminase inhibitors. In T lymphoblasts, under induced conditions, only simultaneous inhibition of both adenosine deaminase activity and adenosine kinase activities resulted in small amounts of adenosine release. Under noninduced conditions, neither B nor T lymphoblasts release adenosine, even in the presence of both adenosine deaminase or adenosine kinase inhibitors. Comparison of B and T cell's enzyme activities involved in adenosine metabolism showed similar activity of AMP deaminase, but the activities of AMP-5'-nucleotidase, adenosine kinase and adenosine deaminase differ significantly. B lymphoblasts release adenosine because of their combination of enzyme activities which produce or utilize adenosine (high AMP-5'-nucleotidase and relatively low adenosine kinase and adenosine deaminase activities). Accelerated ATP degradation in B lymphoblasts proceeds not only via AMP deamination, but also via AMP dephosphorylation into adenosine but its less efficient intracellular utilization results in the release of adenosine from these cells. In contrast, T lymphoblasts release far less adenosine, because they contain relatively low AMP-5'-nucleotidase and high adenosine kinase and adenosine deaminase activities. In T lymphoblasts, AMP formed during ATP degradation is not readily dephosphorylated to adenosine but mainly deaminated to IMP by AMP deaminase. Any adenosine formed intracellularly in T lymphoblasts is likely to be efficiently salvaged back to AMP by an active adenosine kinase. In general, these results may suggest that adenosine can be produced only by selective cells (adenosine producers) whereas other cells with enzyme combination similar to SupT1-T lymphoblasts can not produce significant amounts of adenosine even in stress conditions.
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PMID:Selective adenosine release from human B but not T lymphoid cell line. 239 45

Neplanocin A [(-)-9-[trans-2',trans-3'-dihydroxy-4'-(hydroxymethyl)-cyclopent-4 '- enyl]-adenine] and 9-[trans-2',trans-3'-dihydroxycyclopent-4'-enyl]-adenine (1) and -3-deazaadenine (2) are potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) in mouse L929 cells. When cells were treated for 15 min with varying concentrations of the drugs, the IC95 values (concentration needed to produce 95% inhibition of AdoHcy hydrolase) for neplanocin A, 1, and 2 were determined to be 0.2 microM, 0.5 microM, and 0.5 microM, respectively. Incubation of L929 cells with 1.0 microM concentrations of neplanocin A, 1, or 2 produced rapid inactivation of AdoHcy hydrolase (within 30 min the enzyme was 95% inhibited), which persisted for at least 72 hr. At lower concentrations (0.032 microM), substantial recovery of AdoHcy hydrolase activity was noted after 48 and 72 hr in cultures treated with neplanocin A but not in cultures treated with 1 or 2. L929 cells treated with neplanocin A, 1 or 2 showed a rapid increase in intracellular levels of AdoHcy (as well as the ratio of AdoHcy/S-adenosylmethionine). Cells treated with neplanocin A also contained significant amounts of S-neplanocylmethionine, whereas cells treated with 1 or 2 showed no evidence of the formation of a similar metabolite. When neplanocin A and adenosine were incubated in cell lysates, rapid conversion to neplanocin D and inosine, respectively, were observed, illustrating the affinity of these nucleosides for cellular adenosine deaminase. In contrast, when 1 and 2 were incubated in cell lysates, no evidence for deamination was observed. These data illustrate that compounds 1 and 2 retain the inhibitory activity of neplanocin A toward cellular AdoHcy hydrolase, producing elevated cellular levels of AdoHcy. However, by removing the 4'-hydroxymethyl group from neplanocin A, analogs 1 and 2 are no longer substrates for adenosine deaminase and adenosine kinase.
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PMID:Effects of 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-adenine and -3-deazaadenine on the metabolism of S-adenosylhomocysteine in mouse L929 cells. 245 88

Enzyme activities were studied in peripheral blood lymphocytes from patients infected with, or at risk for, infection with human immunodeficiency virus (HIV). No significant differences were observed in the HIV-infected and HIV-seronegative high-risk patients with regard to enzyme activities of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) and purine nucleoside phosphorylase (EC 2.4.2.1) in peripheral blood. Adenosine deaminase (EC 3.5.4.4) was significantly (P less than 0.02) depressed in asymptomatic HIV-seropositive patients and HIV-seronegative patients at high risk of HIV infection as compared with a healthy HIV-seronegative population. Adenosine kinase (AK, EC 2.7.1.20) was significantly increased in the asymptomatic seropositive (P less than 0.02) and also in the HIV-seronegative high-risk groups (P = 0.01) compared with the normal controls. AK activity was significantly lower in subjects with AIDS than in the asymptomatic (P less than 0.002) and high-risk groups (P less than 0.01). Taken together, these results indicate that adenosine deaminase and AK activities are influenced by the health of the patient, and that measurement of AK activity may prove useful in monitoring the clinical progress of patients with HIV infection.
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PMID:Depressed activities of purine enzymes in lymphocytes of patients infected with human immunodeficiency virus. 254 31

1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil and a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes, myelin and 105,000 g soluble fractions were obtained from six regions of the brain. 2. Hypothyroidism resulted in 2-5-fold increases in membrane-bound 5'-nucleotidase activity in synaptosomal fractions obtained from cerebellum, cortex, striatum and hippocampus. By contrast, myelin 5'-nucleotidase activity was slightly increased only in the medulla oblongata. 3. Hypothyroidism did not change adenosine deaminase activity, but decreased adenosine kinase activity by approx. 40% in soluble fractions obtained from cerebellum, hippocampus, striatum and hypothalamus. 4. It is suggested that these changes in hypothyroidism, in particular the increases in 5'-nucleotidase activity, could enhance the neuromodulatory effect of adenosine to decrease neurotransmitter release.
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PMID:Changes in the activities of adenosine-metabolizing enzymes in six regions of the rat brain on chemical induction of hypothyroidism. 254 78

AMP-sepharose 4B has been widely used as a general ligand affinity chromatography for purification of AMP deaminase, 5'-nucleotidase, adenosine kinase and other adenine nucleotide metabolizing enzymes. Since these enzymes generally differ in their kinetic properties related to the values of Km for AMP and analogous compounds, it was assumed that there may be a specific elution pattern of some of the enzymes which would enable sequential elution from the column during a single run. Using 0.5 M NaCl, 10 mM ATP and 5 mM adenosine as eluting agents, it was possible to separate on AMP-sepharose column AMP deaminase "high Km" and "low Km" 5'-nucleotidase and adenosine kinase. Adenylate kinase, adenosine deaminase and nonspecific phosphatase did not bind to the column. Using human placental extract, AMP deaminase, "high Km" and "low Km" 5'-nucleotidase and adenosine kinase were purified 2.8, 2.9, 105 and 1240 fold, respectively. AMP deaminase and "high Km" 5'-nucleotidase were further separated using phosphocellulose column chromatography and the final purification was 227 and 143 fold, respectively. The specific activities of purified enzyme preparations were 9.1, 1.0, 0.4 and 0.5 mumols/min/mg protein of AMP deaminase, "high Km" 5'-nucleotidase and adenosine kinase, respectively. This approach provides a rapid method for initial purification of these enzymes from crude soluble extracts.
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PMID:The application of affinity chromatography for the separation of "high Km" and "low Km" 5'-nucleotidase and other AMP metabolizing enzymes. 255 31

The transmural distribution of the adenosine-generating enzyme 5'-nucleotidase (5'N) and of the adenosine-degrading enzymes adenosine deaminase (ADA), AMP deaminase (AMP-D) and adenosine kinase (Ado-K) were determined across the walls of left and right ventricles of control and hypertrophic rat hearts. The enzyme distribution across the left ventricle wall (but not across the right wall) of normal hearts was not uniform: 5'N activity shows its highest levels in the subepicardial and in the subendocardial regions, whereas all the other enzyme activities show their lowest levels. A similar pattern of transmural distribution was also detected in other mammalian species (ox and pig). In the experimental cardiac hypertrophy, caused by two different types of chronic cardiac overload, the levels and the profiles of transmural distribution of 5'N and ADA enzyme activities may significantly change across the rat left ventricle wall.
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PMID:The regional distribution of adenosine-regulating enzymes in the left and right ventricle walls of control and hypertrophic heart. 255 11

The monophosphates of the exocyclic amino ribonucleosides, 4-amino- and 4-methoxy-8-(D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine, are potent and specific inhibitors of human erythrocyte and B-lymphoblast PRPP synthetase. The inhibition by MRPP monophosphate is competitive (Ki = 35 microM with the PRPP synthetase cofactor, Pi (Km = 2 mM). The nucleosides are phosphorylated to the active metabolite by adenosine kinase and these nucleoside monophosphates accumulate in the cell. beta-ARPP is a substrate, albeit poor, for adenosine deaminase and solutions of the beta-anomer of this nucleoside and its monophosphate anomerize over time to give alpha- and beta-mixtures. beta-MRPP is more resistant to adenosine deaminase and anomerization of the nucleoside and its monophosphate is negligible. The effect of treatment of cells with the nucleosides is a time-dependent and nearly universal reduction in the nucleotide content which appears to result from a reduction in the availability of PRPP for dependent metabolic pathways. In studies with the WI-L2 lymphoblasts, some of these pathways, de novo and salvage (hypoxanthine and guanine) synthesis of purine nucleotides, are more sensitive to a restriction of PRPP availability than others, i.e. de novo pyrimidine synthesis. The nucleosides have shown promise as therapeutic agents in a mouse leukemia evaluation system but may also have future use in unravelling the complex regulation of PRPP synthetase and the dependent nucleotide synthesis pathways.
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PMID:Potent and specific inhibitors of mammalian phosphoribosylpyrophosphate (PRPP) synthetase. 256 Mar 24

The S-adenosylhomocysteine (SAH) hydrolase inhibitor adenosine dialdehyde was used in isolated guinea pig hearts to determine the contribution of the transmethylation pathway to cardiac adenosine formation. This inhibitor did not alter cardiac hemodynamics but effectively inhibited SAH-hydrolase activity under in vitro and in vivo conditions. In normoxic perfused hearts adenosine dialdehyde (10 microM) caused tissue levels of SAH to linearly increase at a rate of 160 pmol/g/min over 60 min. At the same time adenosine dialdehyde decreased release of adenosine into the coronary effluent perfusate by 16 pmol/min (34%). Hypoxic perfusion (30% O2) of guinea-pig hearts increased release of adenosine from 43 to 3700 pmol/min. However, rate of SAH formation in the presence of adenosine dialdehyde was only slightly enhanced from 160 to 200 pmol/g/min and adenosine dialdehyde did not significantly alter the hypoxia induced adenosine release. Since all experiments were performed in the presence of the adenosine deaminase inhibitor EHNA (5 microM) the results demonstrate: (1) the transmethylation pathway of the heart contributes one third to global cardiac adenosine production under normoxic conditions and provides a constant source of adenosine independent of tissue oxygenation. (2) The majority of SAH-derived adenosine is salvaged most likely via adenosine kinase. (3) The hypoxia induced adenosine production is predominantly derived from enhanced 5' AMP hydrolysis.
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PMID:Contribution of S-adenosylhomocysteine to cardiac adenosine formation. 277 14

The mechanism of the depletion of ATP, recorded in the erythrocytes of adenosine deaminase-deficient children and of leukemia patients treated with deoxycoformycin, was investigated in normal human erythrocytes treated with this inhibitor of adenosine deaminase. Deoxyadenosine, which accumulates in both clinical conditions, provoked a dose-dependent accumulation of dATP, depletion of ATP, and increases in the production of inosine plus hypoxanthine. Concomitantly, there was an increase of AMP and IMP, but not of adenosine, indicating that catabolism proceeded by way of AMP deaminase. A series of nucleoside analogues (9-beta-D-arabinofuranosyladenine, N6-methyladenosine, 6-methylmercaptopurine ribonucleoside, tubercidin, ribavirin, and N-1-ribosyl-5-aminoimidazole-4-carboxamide riboside) also stimulated adenine nucleotide catabolism and increased AMP and IMP to various extents. The effects of deoxyadenosine and of the nucleoside analogues were prevented by 5'-iodotubercidin, an inhibitor of adenosine kinase. Strikingly, they were reversed if the inhibitor was added after the accumulation of nucleotide analogues and initiation of adenine nucleotide catabolism. Further analyses revealed linear relationships between the rate of phosphorylation of deoxyadenosine and nucleoside analogues and the increase in AMP and between the elevation of the latter above a threshold concentration of 10 microM and the rate of adenine nucleotide catabolism. Kinetic studies with purified erythrocytic AMP deaminase, at physiological concentrations of its effectors, showed that the enzyme is nearly inactive up to 10 microM AMP and increases in activity above this threshold. We conclude that the main mechanism whereby deoxyadenosine and nucleoside analogues stimulate catabolism of adenine nucleotides by way of AMP deaminase in erythrocytes is elevation of AMP, secondary to the phosphorylation of the nucleosides.
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PMID:Mechanism of adenosine triphosphate catabolism induced by deoxyadenosine and by nucleoside analogues in adenosine deaminase-inhibited human erythrocytes. 278 93

1. Adipocytes were isolated from epididymal white fat and interscapular brown fat of male rats, and activities of 5'-nucleotidase, adenosine deaminase and adenosine kinase were measured in cell extracts. 2. 5'-Nucleotidase activity in white adipocytes was increased in streptozotocin-diabetes, decreased in hypothyroidism and increased with age. That activity in brown adipocytes was unchanged in diabetes, decreased in hypothyroidism and increased with age. 5'-Nucleotidase activity was higher in white adipocytes from female rats. 3. Adenosine deaminase activity in white adipocytes was increased in diabetes, decreased in hypothyroidism and increased with age. That activity in brown adipocytes was decreased in diabetes and hypothyroidism. 4. Adenosine kinase activity in both cell types was unchanged in diabetes or hypothyroidism, but increased with age.
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PMID:Enzymes involved in adenosine metabolism in rat white and brown adipocytes. Effects of streptozotocin-diabetes, hypothyroidism, age and sex differences. 282 32


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