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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study sought to evaluate the effect of a newly synthesized selenium compound, dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) on the activities of delta-aminolevulinate dehydratase and Na+/K+-ATPase in the rat brain. The glutathione peroxidase mimetic activity of the two compounds as well as their ability to oxidize mono- and di- thiols were also evaluated. The antioxidant effects were tested by measuring the ability of the compounds to inhibit the formation of thiobarbituric acid reactive species and also their ability to inhibit the formation of protein carbonyls. The results show that DPDS exhibited a higher glutathione peroxidase mimetic activity as well as increased ability to oxidize di-thiols than DCDS. In addition, while DPDS inhibited the formation of thiobarbituric acid reactive species and protein carbonyls, DCDS exhibited a prooxidant effect in all the concentration range (20-167 microM) tested. Also the activities of cerebral delta-aminolevulinate dehydratase and Na+/K+ ATPase were significantly inhibited by DPDS but not by DCDS. In addition, the present results suggested that the inhibition of Na+/K+ ATPase by organodiselenides, possibly involves the modification of the thiol group at the ATP binding site of the enzyme. In conclusion, the results of the present investigation indicated that the non-selenium moiety of the organochalcogens can have a profound effect on their antioxidant activity and also in their reactivity towards SH groups from low-molecular weight molecules and from brain proteins.
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PMID:Comparative studies on dicholesteroyl diselenide and diphenyl diselenide as antioxidant agents and their effect on the activities of Na+/K+ ATPase and delta-aminolevulinic acid dehydratase in the rat brain. 1771 May 41

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is a selenium-containing antioxidant demonstrating anti-inflammatory and cytoprotective properties in mammalian cells and cytotoxicity in lower organisms. The mechanism underlying the antimicrobial activity of ebselen remains unclear. It has recently been proposed that, in lower organisms like yeast, the plasma membrane H+-ATPase (Pma1p) could serve as a potential target for this synthetic organoselenium compound. Using yeast and bacteria, the present study found ebselen to inhibit microbial growth in a concentration- and time-dependent manner, and yeast and Gram-positive bacteria to be more sensitive to this action (IC50 approximately 2-5 microM) than Gram-negative bacteria (IC50 < 80 microM). Washout experiments and scanning electron microscopic analysis revealed ebselen to possess fungicidal activity. In addition, ebselen was found to inhibit medium acidification by PMA1-proficient haploid yeast in a concentration-dependent manner. Additional studies comparing PMA1 (+/-) and PMA1 (+/+) diploid yeast cells revealed the mutant to be more sensitive to treatment with ebselen than the wild type. Ebselen also inhibited the ATPase activity of Pma1p from S. cerevisiae in a concentration-dependent manner. The interaction of ebselen with the sulfhydryl-containing compounds L-cysteine and reduced glutathione resulted in the complete and partial prevention, respectively, of the inhibition of Pma1p ATPase activity by ebselen. Taken together, these results suggest that the fungicidal action of ebselen is due, at least in part, to interference with both the proton-translocating function and the ATPase activity of the plasma membrane H+-ATPase.
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PMID:Evaluation of the antimicrobial activity of ebselen: role of the yeast plasma membrane H+-ATPase. 1791 95

The distribution of selenium in mammals has been recently shown to be mediated primarily by selenoprotein P. Even in the absence of selenoprotein P, selenium is distributed from the liver into all organs and tissues when supplemented in the diet. The form of selenium that is actively taken up by mammalian cells at trace concentrations has yet to be determined. We used a human keratinocyte model to determine whether reduction of the oxyanion selenite (SeO(3)(2-)) to the more reduced form of selenide (HSe(-)) would affect uptake. Indeed a reduced form of selenium, presumably selenide, was actively transported into keratinocytes and displayed saturation kinetics with an apparent K(m) of 279 nM. ATPase inhibitors blocked the uptake of selenide, as did the competing anions molybdate and chromate, but not sulfate. These results suggest that the small molecule form of selenium that is distributed in tissues is hydrogen selenide, despite its sensitivity to oxygen and reactivity to thiols.
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PMID:High affinity selenium uptake in a keratinocyte model. 1815 36

Diabetes is characterized with increased oxidant stress, vasculopathy, and neuropathy. In diabetic vasculopathy, the observed thickening of the media and intima is not only a result of vascular smooth muscle cell proliferation but also due to modification of the extracellular matrix by these cells. Also, there is hampered membrane function and a reduction in sodium pump expression in the vessels of the diabetic animals. Selenium, being a trace element, has both insulinomimetic and antioxidant effects. Thus, we hypothesized that selenium treatment will reduce proliferation, restore physiology, and correct increased proliferation signaling of diabetic aorta. Diabetes was induced by streptozotocin (50 mg/kg body weight), and rats were then treated with sodium selenate (15 mumol/kg body weight/day) for 4 weeks. Our data from diabetic rats showed an increase in proliferation rate and matrix metalloproteinase activity in aortic cell cultures. We observed marked increases in MAPK phosphorylation and caveolin 1 expression but a decrease in Na(+)/K(+) ATPase activity in diabetic rat aorta homogenates. Selenium treatment resulted in complete normalization of the above parameters to control level, while it increased Na(+)/K(+) pump activity by 40%. Our results suggest that selenium treatment of diabetics can play beneficial role in protecting vascular architecture and function against diabetes-induced pathology.
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PMID:Selenium inhibits proliferation signaling and restores sodium/potassium pump function of diabetic rat aorta. 1870 74

It has been suggested that oxidative stress products play an important role in the etiology of epilepsy. We investigated the effects of selenium (Se) administration on topiramate (TPM)- and pentylentetrazol (PTZ)-induced brain toxicity in rats. Forty male Wistar rats were divided into five equal groups. The first and second groups were used as the control and PTZ groups, respectively. TPM, 50 mg, and Se, 0.3 mg, were administered to rats constituting the third and fourth groups, respectively, for 7 days. The combination of 50 mg TPM and Se was given to animals in the fifth group for 7 days. At the end of 7 days all groups except the first received a single dose of PTZ. Brain cortex samples were taken at 3 h of PTZ administration. PTZ resulted in a significant increase in brain cortex and microsomal lipid peroxidation (LP) levels, number of spikes, and epileptiform discharges on the EEG, although brain cortex vitamin E, brain cortex and microsomal reduced glutathione (GSH), and microsomal calcium (Ca) levels, Ca(2+)-ATPase activities, and latency to first spike on the EEG were decreased by PTZ. LP, GSH, vitamin E, and Ca levels and Ca(2+)-ATPase activities were increased by both Se and TPM, although vitamin A and C concentrations were increased by Se only. There were no effects of TPM and Se on brain cortex and microsomal glutathione peroxidase, brain cortex nitric oxide, or beta-carotene levels. In conclusion, TPM and selenium caused protective effects on PTZ-induced brain injury by inhibiting free radical production, regulating calcium-dependent processes, and supporting the antioxidant redox system.
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PMID:Selenium and topiramate modulates brain microsomal oxidative stress values, Ca2+-ATPase activity, and EEG records in pentylentetrazol-induced seizures in rats. 1894 5

The Saccharomyces cerevisiae gene YPK9 encodes a putative integral membrane protein which is 58% similar and 38% identical in amino acid sequence to the human lysosomal P(5B) ATPase ATP13A2. Mutations in ATP13A2 have been found in patients with Kufor-Rakeb syndrome, a form of juvenile Parkinsonism. We report that Ypk9p localizes to the yeast vacuole and that deletion of YPK9 confers sensitivity for growth for cadmium, manganese, nickel or selenium. These results suggest that Ypk9p may play a role in sequestration of divalent heavy metal ions. Further studies on the function of Ypk9p/ATP13A2 may help to define the molecular basis of Kufor-Rakeb syndrome and provide a potential link to environmental factors such as heavy metals contributing to some forms of Parkinsonism.
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PMID:Cd2+, Mn2+, Ni2+ and Se2+ toxicity to Saccharomyces cerevisiae lacking YPK9p the orthologue of human ATP13A2. 1934 71

PMA1 is a yeast gene that codes for the plasma membrane H(+)-ATPase, a protein commonly referred to as Pma1p. Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is a synthetic selenium-containing compound that has recently been shown to display antimicrobial activity owing to its ability to inhibit Pma1p. Ebselen is able to block the activity of Pma1p not only in opportunistic pathogens such as Cryptococcus neoformans and Candida albicans but also in nonpathogenic yeasts such as Saccharomyces cerevisiae. A series of in vitro studies aimed at evaluating the antifungal activity of ebselen were performed. At low concentrations (<10 microM), ebselen was fungistatic against three strains of S. cerevisiae (IC(50) approximately 3 microM) and one fluconazole-resistant strain of C. albicans (IC(50) approximately 6 microM), and at a high concentration (30 microM) it was fungicidal against C. albicans. Moreover, ebselen was found to inhibit medium acidification by the fluconazole-resistant strain of C. albicans in a concentration-dependent manner. In comparison to currently used antifungal agents represented by azole (itraconazole, ketoconazole, fluconazole) and polyene (amphotericin B) compounds, ebselen was at least 10-fold more potent than fluconazole but less active than the other compounds tested. The present results suggest that the growth inhibitory activity of ebselen toward fluconazole-resistant yeast cells is due, at least in part, to inhibition of Pma1p. Ebselen may also serve as a useful agent in the treatment of infections caused by fluconazole-resistant fungi.
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PMID:Growth inhibitory action of ebselen on fluconazole-resistant Candida albicans: role of the plasma membrane H+-ATPase. 1943 23

This study investigated the hemolytic and genotoxic effect of different organoselenium and organotellurium compounds in human blood cells, as simple tests for screening the toxicity of organochalcogenides. For osmotic fragility (OF) test, samples of total blood were incubated with the organochalcogens at 4, 8, 50, 75 and 100 microM or vehicle (DMSO) for 90 min at 37 degrees C. The EC(50) values for hemolysis were significantly increased in erythrocytes exposed to diphenyl selenide (II), diphenyl diselenide (III), diphenyl telluride (IV), diphenyl ditelluride (V), (S)-2-amino-1-diselenide-3-methylpropanyl (IX), butyl(styryl)telluride (XIII) and 2-(butyltellurium)furan (XIV) at higher concentrations tested. The exposure of erythrocytes to organochalcogens diphenyl diselenide (II) and butyl(styryl)telluride (XIII), which had greater hemolytic effect, did not modify catalase activity, reactive oxygen species (ROS) production and -SH content. On the other hand, Na(+)/K(+) ATPase activity of erythrocyte ghosts was significantly inhibited by the compounds diphenyl diselenide (II) and butyl(styryl)telluride (XIII) (P<0.05) in a concentration-dependent manner. The inhibition of Na(+)/K(+) ATPase activity was completely reversed by dithiothreitol (DTT); indicating reaction of these organochalcogens with thiol groups of the enzyme. The thiol oxidase activity of the compounds II and XIII was supported by the fact that the rate of DTT oxidation was increased significantly by both chalcogens. In the higher concentrations, the compounds (II) and (XIII) were strongly genotoxic and cytotoxic to human leukocytes cells, as verified by the DNA damage and cell viability evaluation. Our results suggest that at relatively high concentration organochalcogenides exhibit hemolytic and genotoxic action in human blood cells, which are probably linked to their thiol oxidase activity and preferential interaction with sulfhydryl groups critical to enzymes.
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PMID:Hemolytic and genotoxic evaluation of organochalcogens in human blood cells in vitro. 1947 62

Selenium (Se) is an essential element that can be toxic at concentrations slightly greater than those required for homeostasis. The main chronic toxic effects of Se in fish are teratogenic deformities, but Se can also activate the physiological stress response and redox cycle with reduced glutathione causing oxidative damage. Rainbow trout, Oncorhynchus mykiss, appear to be more sensitive to Se than brook trout, Salvelinus fontinalis. The objective of this study was to compare the physiological stress response (plasma cortisol, glucose, triiodothyronine, thyroxine, gill Na+/K+ ATPase, cortisol secretory capacity, K and liver somatic index) and oxidative stress biomarkers (liver GSH, GPx, lipid peroxidation, vitamin A and vitamin E) in rainbow trout (RNTR) and brook trout (BKTR) collected from reference and Se-exposed streams. The physiological stress response was not impaired (cortisol secretory capacity unchanged); although there were species differences in plasma cortisol and plasma glucose levels. Liver GSH, GPx and vitamin levels were higher in RNTR than BKTR, but lipid peroxidation levels were not different. The elevated GSH reserves may make RNTR more sensitive to Se-induced lipid peroxidation, but this may be offset by the RNTR's higher antioxidant (GPx and vitamin) levels. Species-specific biochemical differences may mediate differences in Se sensitivity and be used in aquatic Se risk assessments.
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PMID:The physiological stress response and oxidative stress biomarkers in rainbow trout and brook trout from selenium-impacted streams in a coal mining region. 1962 77

Mechanistically similar selenophosphate synthetases (SPS) have been isolated from different organisms. SPS from Escherichia coli is an ATP-dependent enzyme with a C-terminal glycine-rich Walker sequence that has been assumed to take part in the first step of ATP binding. Three C-terminally truncated mutants of SPS, containing the N-terminal 238 (SPS(238)), 262 (SPS(262)), and 332 (SPS(332)) amino acids of the 348-amino-acid protein, have been extracted from cell pellets, and two of these (SPS(262) and SPS(332)) have been purified to homogeneity. SPS(238) has been obtained in a highly purified form. Binding of the fluorescent ATP-derivative TNP-ATP and Mn-ATP to the proteins was examined for all truncated mutants of SPS and a catalytically inactive C17S mutant. It has been shown that TNP-ATP can be used as a structural probe for ATP-binding sites of SPS. We observed two TNP-ATP binding sites per molecule of enzyme for wild-type SPS and SPS(332) mutant and one TNP-ATP binding site for SPS(238) mutant. The stoichiometry of Mn-ATP-binding was 2 mol of ATP per mol of protein determined with [(14)C]ATP by HPLC gel-filtration column chromatography under saturating conditions. The binding stoichiometries for SPS(332), SPS(262), and SPS(238) were 2, 1.6, and 1, respectively. The C17S mutant exhibits about one third of wild type SPS TNP-ATP-binding ability and converts 12% of ATP in the ATPase reaction to ADP in the absence of selenide. The C-terminus contributes two thirds to the TNP-ATP binding; SPS(238) likely has one ATP-binding site removed by truncation.
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PMID:Binding of ATP and its derivatives to selenophosphate synthetase from Escherichia coli. 2116 49


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