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 essential tRNA-specific adenosine deaminase catalyzes the deamination of adenosine to inosine at the wobble position of tRNAs. This modification allows for a single tRNA species to recognize multiple synonymous codons containing A, C, or U in the last (3'-most) position and ensures that all sense codons are appropriately decoded. We report the first combined structural and kinetic characterization of a wobble-specific deaminase. The structure of the Escherichia coli enzyme clearly defines the dimer interface and the coordination of the catalytically essential zinc ion. The structure also identifies the nucleophilic water and highlights residues near the catalytic zinc likely to be involved in recognition and catalysis of polymeric RNA substrates. A minimal 19 nucleotide RNA stem substrate has permitted the first steady-state kinetic characterization of this enzyme (k(cat) = 13 +/- 1 min(-)(1) and K(M) = 0.83 +/- 0.22 microM). A continuous coupled assay was developed to follow the reaction at high concentrations of polynucleotide substrates (>10 microM). This work begins to define the chemical and structural determinants responsible for catalysis and substrate recognition and lays the foundation for detailed mechanistic analysis of this essential enzyme.
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PMID:Structural and kinetic characterization of Escherichia coli TadA, the wobble-specific tRNA deaminase. 1670 May 51

In this study, an attempt was made to elucidate the combined effect of 2'-deoxycoformycin (DCF), an adenosine deaminase inhibitor, with a water extract of Cordyceps sinensis (WECS), on the growth curves of mouse melanoma and lung carcinoma cells. Sub-confluent cells were harvested with an EDTA trypsin solution, and resuspended to appropriate concentrations in DMEM containing 10% fetal bovine serum. Using 1x10(5) cells/2 ml in each well of a 12-well culture plate, cells were incubated for 24, 48 and 72 h in the presence of WECS alone, or WECS plus DCF in a CO2 incubator at 37 degrees C. Duplicate samples of viable cells were enumerated with a Coulter counter. The antitumor effect of WECS on the growth curves of tumor cell lines increased over 3-fold in combination with DCF. These results suggest that DCF has a remarkable reinforcement effect on the antitumor activity of WECS. DCF is a potent adjuvant for WECS.
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PMID:Reinforcement of antitumor effect of Cordyceps sinensis by 2'-deoxycoformycin, an adenosine deaminase inhibitor. 1743 79

The effects of some plant growth regulators (PGRs), 2,3,5-triiodobenzoic acid (TIBA), Naphthaleneacetic acid (NAA) and 2,4-Dichlorofenoxyacetic acid (2,4-D), at sublethal concentrations on antioxidant defense system [glutathione peroxidases (GPx), reduced glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT)], immune potential enzymes [adenosine deaminase (ADA) and myeloperoxidase (MPO)], and lipid peroxidation content [Malondialdehyde, (MDA)] were investigated in lung and speen tissues of rats. Sprague-Dawley albino rats were exposed to 0, 50, or 100 ppm (parts per million) TIBA, NAA, or 2,4-D in drinking water ad libitum for 25 days continuously. According to the results, MDA concentration significantly increased in the tissues treated with 100 ppm dosage of NAA or 2,4-D without any change in the tissues of rats treated with both dosage of TIBA. The GSH depletion in the spleen tissue of rats treated with both the dosage of NAA and 2,4-D were found to be significant. Also, GSH level in the spleen was significantly reduced with 100 ppm of 2,4-D and NAA. The activity of antioxidant enzymes were also seriously affected by PGRs; GPx significantly decreased in the lung of rats treated with both dosages of the PGRs, whereas GPx activity in the spleen were significantly increased with 100 ppm dosage of 2,4-D and NAA. On the other hand, CAT activity significantly decreased in the lung of rats treated with both dosages of NAA, 100 ppm of 2,4-D and 50 ppm of TIBA, and also in the spleen treated with 50 ppm NAA and 2,4-D. The ancillary enzyme GR activity significantly decreased in the spleen with both doses of the PGRs, also in the lung treated with both dosages of 2,4-D, 50 ppm of NAA and 100 ppm of TIBA. The drug metabolizing enzyme GST activity significantly reduced in the lung of rats treated with both dosages of the PGRs and also in the spleen treated with 100 ppm dosage of 2,4-D and TIBA and 50 ppm of NAA. Meanwhile, immune potential enzyme MPO activity significantly increased in the spleen of rats treated with both doses of NAA and TIBA whereas ADA activity significantly decreased in the spleen of rats treated with 100 ppm dose of NAA and TIBA. The observations presented led us to conclude that the administrations of subacute NAA, 2,4-D, and TIBA promote MDA content, inhibit the antioxidative defense system and activate or inhibit immune potential enzymes in the rat's spleen and lung tissues. These data suggest that PGRs produced substantial organ toxicity in the lung and spleen during the period of a 25-day subacute exposure.
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PMID:Determination of toxicity of subacute treatment of some plant growth regulators on rats. 1800 Aug 51

The aim of this study was to investigate the anti-inflammatory efficacy of an aqueous extract (AE), and its butanolic (BuOH) and aqueous residual (AR) fractions, derived from the rhizome of Solidago chilensis in inflammation caused by carrageenan in mice. Solidago chilensis Meyen rhizome was extracted using hot water at 90 degrees C under infusion. The extract was filtered and lyophilized. Part of the aqueous extract was fractionated with n-BuOH, resulting in butanolic (BuOH) and aqueous residual (AR) fractions. Adult Swiss mice were used in the in-vivo experiments. We evaluated the effect of rhizome aqueous extract of Solidago chilensis and these two derived fractions on the inflammation induced by carrageenan in the mouse model of the air pouch. The aqueous extract and its derived fractions significantly inhibited leucocytes, neutrophils, exudation, myeloperoxidase and adenosine deaminase activity, as well as nitric oxide, interleukin-1 beta (IL-1beta), neutrophil chemokine (KC) and tumour necrosis factor-alpha (TNF-alpha) levels (P < 0.05). Indometacin and dexamethasone inhibited all the studied inflammatory parameters (P < 0.01) with the exceptions that indometacin did not inhibit TNF-alpha levels and dexamethasone did not inhibit KC levels (P > 0.05). These results indicate that Solidago chilensis has a significant anti-inflammatory action on acute inflammatory responses and that its inhibitory activity may be due not only to the inhibition of proinflammatory mediators, but also to the inhibition of leucocyte infiltration.
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PMID:The anti-inflammatory modulatory role of Solidago chilensis Meyen in the murine model of the air pouch. 1838 Sep 25

The aim of this experimental study was to investigate the possible role of nitric oxide (NO) and the activities of adenosine deaminase (ADA) and xanthine oxidase (XO) in the pathogenesis of isoniazid (INH)-induced oxidative damage in red blood cells (RBCs), and also to show the effect of caffeic acid phenethyl ester (CAPE) and erdosteine, antioxidants, in decreasing this toxicity. A total of 25 adult male rats were divided into four experimental groups as follows: control group (n = 7), INH-treated group (n = 6), INH + CAPE-treated group (n = 6), and INH + erdosteine-treated group (n = 6). INH, INH-CAPE, and INH-erdosteine-treated groups were treated orally with INH 50 mg/kg daily and with the tap water for 15 days. Control group was given only tap water. CAPE was intraperitoneally injected for 15 days at a dose of 10 micromol/kg. Erdosteine was treated orally for 15 days at a dose of 10 mg/kg/day. The injection of INH led to a significant increase in the activities of ADA, XO, and NO levels in RBCs of rats. Co-treatment with CAPE caused a significant decrease in the activities of ADA and XO and the levels of NO in RBCs. In addition, co-treatment with erdosteine caused a significant decrease in the activities of ADA and XO and the levels of NO in RBCs. The results of this study showed that ADA, XO, and NO may play an important role in the pathogenesis of INH-induced oxidative stress in RBCs. CAPE and erdosteine may have protective potential in this process and they may become a promising drug in the prevention of this undesired side effect of INH.
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PMID:Protective role of caffeic acid phenethyl ester and erdosteine on activities of purine-catabolizing enzymes and level of nitric oxide in red blood cells of isoniazid-administered rats. 1903 79

Plasmodium falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation. Methylthioadenosine (MTA) is a substrate for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation [Larson, E. T., et al. (2008) J. Mol. Biol. 381, 975-988]. Here, the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172. Treatment of P. falciparum cultures with coformycin or MT-coformycin in the presence of MTA is effective in inhibiting parasite growth.
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PMID:Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. 1972 41

Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20-100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-alpha/beta activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
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PMID:Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors. 2037 26

The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition. The rate-determining step is the proton transfer from Zn-OH to 6-NH(2) of the tetrahedral intermediate, in which His238 serves as a proton shuttle for the proton transfer. The calculated kinetic isotope effects agree well with the experimental data, and calculated activation energy is also consistent with the experimental reaction rate.
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PMID:A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase. 2057 11

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition, with only 45 cases recorded to date, characterized by infiltration of the meninges by glial cells without evidence of primary tumor in the brain or spinal cord parenchyma. Here, we describe a patient with PDLG who was managed with tuberculostatic drugs owing to multiple findings that were suggestive of tuberculous meningitis. A 19-year-old woman presented with headaches and behavioral changes. A sudden decrease in visual acuity with papilledema, bilateral sixth nerve palsies, and neck stiffness developed. Lumbar puncture showed elevated opening pressure (50 cm H2O). Cerebrospinal fluid (CSF) analysis showed glucose 30 mg/dL, protein 26.5 mg/dL, white blood cell count 150 (60% lymphocytes, 40% neutrophils). The second sample of CSF provided adenosine deaminase activity 21.9 U/L. Polymerase chain reaction for Koch's bacillus was positive in the third CSF sample. Magnetic resonance imaging revealed meningeal thickening of the quadrigeminal cistern, tentorium cerebelli, cerebral convexity, and spinal cord, with gadolinium enhancement in nodular lesions. The patient died 22 weeks after symptom onset owing to brainstem infarction. Postmortem pathologic studies revealed PDLG. This entity should be included in the differential diagnosis of tuberculous meningitis that does not respond to treatment with antituberculous drugs. Surgical biopsy should be considered in contrast-enhanced areas in magnetic resonance imaging.
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PMID:Primary diffuse leptomeningeal gliomatosis mimicking meningeal tuberculosis. 2153 87

The aim of the present study was to investigate the effects of grape seed extract (GSE) supplementation on exercise performance and oxidative stress in acutely and chronically exercised rats. A total of sixty-four male rats were used in the study. Rats were divided into six groups: control, chronic exercise control, acute exercise control (AEC), GSE-supplemented control, GSE-supplemented chronic exercise and GSE-supplemented acute exercise groups. Chronic exercise consisted of treadmill running at 25 m/min, 45 min/d, 5 d a week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. GSE were given at 100 mg/kg of body weight with drinking water for 6 weeks. Plasma was separated from blood samples for the analysis of oxidative stress markers. There was no significant difference in time of exhaustion between the acute exercise groups. Plasma malondialdehyde (MDA) levels were higher in the acute exercise groups and lower in the chronic exercise groups. GSE supplementation decreased MDA levels. Xanthine oxidase and adenosine deaminase activities were higher in the AEC group compared to all the other groups. NO levels were increased with both chronic exercise and GSE supplementation. Superoxide dismutase and glutathione peroxidase activities were lower in the acute exercised groups and higher in the chronic exercised groups. GSE supplementation caused an increase in antioxidant enzyme activities. In conclusion, GSE supplementation prevents exercise-induced oxidative stress by preventing lipid peroxidation and increasing antioxidant enzyme activities.
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PMID:Effects of grape seed extract supplementation on exercise-induced oxidative stress in rats. 2201 89


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