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)

Formation of reactive oxygen species and disfunction of the excitatory amino acid (EAA) system are thought to be key events in the development of neuronal injury in several acute and long-term neurodegenerative diseases. Recent evidence suggests that the two phenomena may be interdependent. The present study is aimed at exploring possible molecular mechanisms underlying oxygen radical-EAA interaction. Exposure of cortical astrocytic cultures to either xanthine + xanthine oxidase (X/XO), a free radical-generating system, or hydrogen peroxide (H2O2) results in a marked decrease of high-affinity glutamate transport. Within 10 min of X/XO application, uptake falls to approximately 60% of its control value. In parallel no detectable release of lactate dehydrogenase occurs. X/XO effect is abolished in the presence of a mixture of scavenger enzymes (superoxide dismutase+catalase) or by the disulfide-reducing agents glutathione and dithiothreitol (DTT), but not by lipophilic antioxidants or ascorbate. The time course of inhibition shows an almost linear decline of glutamate transport during cell exposure to free radicals, while upon their inactivation the decline stops but established inhibition persists for at least 1 hr. In this situation, application of DTT significantly restores transport function. These data suggest that free radicals inhibit glutamate uptake primarily by long-lasting oxidation of protein sulfhydryl (SH) groups. Chemical modifiers of free SH groups, such as p-chloromercuribenzoate and N-ethylmaleimide, also induce uptake inhibition. Na+/K+ ATPase is a known target of oxygen radicals and may be involved in glutamate uptake inhibition. Indeed, ouabain, a blocker of the pump, reduces uptake in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. 791 Feb 3

Free radicals produced by water radiolysis were used to study the inactivation of the enzymatic activity of the Na,K-ATPase. A decrease of the activity to virtually zero with a mono-exponential dependence on the radiation dose was observed. The inactivation process is initiated by hydroxyl radicals. This was shown by the effect of appropriate radical scavengers such as t-butanol, formate and vitamin C. In all cases a significant increase in the characteristic D37 dose of inactivation was observed. Inactivation was found to show a so-called inverse dose-rate effect, i.e., the sensitivity of the enzyme to radical attack is increased if the dose rate is reduced. The data were found to agree with the relationship 1/D37 approximately 1/D1/2, which is known to be a strong indicator of a radical chain mechanism. This means that the inactivation, after initiation by single radicals, is amplified by a subsequent chain mechanism.
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PMID:Inactivation of the Na, K-ATPase by radiation-induced free radicals. Evidence for a radical-chain mechanism. 795 79

Artemisinin is an effective antimalarial agent, and its action on the malarial parasite is suggested to be mediated by oxidative processes. Since malarial parasites contain a high concentration of hemin, and hemin may induce the formation of reactive oxygen species, we investigated the interaction of artemisinin, iron and hemin. We used erythrocyte membrane-bound Ca2+ pump ATPase (basal) and calmodulin (CaM)-activated Ca2+ pump ATPase as our model. Membranes were incubated with artemisinin in the presence or absence of iron-ascorbate or hemin at 37 degrees for 1 hr. Following incubation, ATPase activity was measured. Our results showed that artemisinin (500 microM) had no effect on ATPase activities. However, artemisinin enhanced the inhibitory effect of iron (50 microM)-ascorbate (500 microM) on ATPase activity (46.3 +/- 3.9 vs 63 +/- 2.1% for basal; 57.2 +/- 2.5 vs 74.8 +/- 2.1% for CaM-activated). Desferrioxamine (DFO, 200 microM) blocked significantly the effect of iron-ascorbate-artemisinin on ATPases (P < 0.01). Hemin inhibited ATPase activity in a concentration-dependent fashion. Artemisinin enhanced hemin (10 microM)-induced inhibition of basal (36.0 +/- 6.0 vs 73.7 +/- 3.0%) and CaM-activated Ca2+ pump ATPase (31.6 +/- 2.8 vs 70.0 +/- 1.5%). Iron chelators (DFO, ferene, 8-hydroxyquinoline, 1,10-phenanthroline, and 1,2-dimethyl-3-hydroxypyrid-4-one) had no effect on artemisinin plus hemin-induced enzyme inhibition. Catalase (2000 U/mL) had a minor effect on the artemisinin-hemin or hemin-mediated effect. Thiourea (1 mM) had no effect. However, superoxide dismutase (500 U/mL) and dithiothreitol blocked artemisinin-hemin or hemin-mediated ATPase inhibition significantly (P < 0.001). In conclusion, these results suggest that, in our model, artemisinin enhances the damage of hemin-induced ATPases via oxidation of thiol groups on the enzymes. Free iron or hydroxyl radical does not seem to be involved. This interaction between artemisinin and hemin may contribute to the antimalarial action of artemisinin against malarial parasites.
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PMID:Enhancement of hemin-induced membrane damage by artemisinin. 808 Apr 46

The H(+)-ATPase from reticulocyte endosomes was purified and reconstituted into liposomes, and protein-dependent iron transport was observed. Reconstitution of the H(+)-ATPase into liposomes was performed by sonicating a lipid mixture, with a composition similar to the reticulocyte plasma membrane, in a buffer containing ferric citrate. The nonencapsulated iron:citrate was removed by gel filtration and the proteoliposomes diluted into 1 mM FerroZine. Upon addition of ascorbate, an initial efflux of 2.9 +/- 0.3 x 10(-2) mumol of iron/mg of ATPase/min and 56 +/-7% of total internal Fe(II) was detected by formation of the Fe(II)-FerroZine complex with an absorbance at 562 nm or radioactivity of 59Fe(II)-FerroZine following separation using gel filtration. Both thiosulfate and ferrocyanide could substitute for ascorbate. Citrate or EGTA could substitute for FerroZine. The initial rate of Fe(II) efflux was decreased by 41 or 17% using 100 microM of the cation channel inhibitor N,N'-dicyclohexylcarbodiimide or 70 microM of the ATP hydrolysis inhibitor N-ethylmaleimide, respectively, but was unaffected by the presence of ATP. The amount of iron transported was decreased 51 or 39% by 100 microM N,N'-dicyclohexylcarbodiimide or 70 microM of the ATPase inhibitor 7-chloro-4-nitrobenz-2-oxa-1,3-diazole. The amount of Fe(III) transport was 80% lower than Fe(II) when reductants were not present internally or externally although the apparent rate constants were identical when ascorbate was externally present. These results suggest that this vacuolar H(+)-ATPase may transport iron.
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PMID:The H(+)-ATPase from reticulocyte endosomes reconstituted into liposomes acts as an iron transporter. 814 5

It was reported previously that dietary ascorbate (ASC) delays the development of galactose-induced cataract in guinea pigs compared to the rate which is observed in ASC-deficient animals. Experiments were conducted to explore the possible mechanism of this phenomenon. Guinea pigs were fed for a period of up to 4 weeks either a normal diet (1 g ASC/kg diet) or a scorbutic diet (< 0.04 g ASC/kg diet) combined with 10% galactose in the drinking water. After 2 weeks, levels of ASC in animals on the scorbutic diet decreased by 95% in the aqueous humor and by 78% in the lens. Slit lamp examination showed that galactose-induced vacuoles in the lens equator formed at a significantly faster rate in the scorbutic animals. However, examination of biochemical parameters in whole lenses of the two groups of animals after 2 weeks showed no significant differences with regard to accumulation of galactose and galactitol, decreases in the levels of myoinositol, taurine and GSH or changes in cation concentrations. In order to examine possible regional changes in the lenses, various parameters were studied in the lens capsule-epithelium. On day 4, the capsule epithelia of scorbutic animals on a galactose diet had a content of galactitol two-and-a-half times higher than that of normal galactose-fed animals. Scorbutic conditions also intensified the loss of Na(+)-K+ ATPase activity in the lens capsule-epithelium caused by galactose feeding. Oxidized glutathione was not detectable in the lens capsule epithelia of any of the animals studied. Hexose monophosphate shunt activity was elevated in lenses of normal galactose-fed animals during the first hour of culture after death whereas lenses of scorbutic galactose-fed animals were not. Consistent with the in vivo findings, galactitol accumulation in dog lens epithelial cells exposed to 30 mM galactose was significantly inhibited by the presence of either ASC or dehydroascorbate (DHA) in the medium. Hexose monophosphate shunt activity in the cells was stimulated to two-and-a-half times its initial level by either 1 mM DHA or 30 mM galactose and slightly more than three-fold by a combination of the two challenges. The results suggest that decreased polyol accumulation in the lens epithelium of the normal galactose-fed guinea pig, which has a high level of ASC in the aqueous humor, accounts for the delay in onset of cataract compared to that for the ASC-deficient animal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A physiological level of ascorbate inhibits galactose cataract in guinea pigs by decreasing polyol accumulation in the lens epithelium: a dehydroascorbate-linked mechanism. 815 13

The fluorescent polyunsaturated parinaric acid (PnA) incorporated in sarcoplasmic reticulum membranes (SR) was used to probe the initial stages of membrane lipid peroxidation. The experimental set up of the PnA assay was investigated by means of several peroxidation initiators to ascertain peroxidation conditions. This assay in SR is particularly useful to evaluate the membrane susceptibility to peroxidation and to ascertain suitable conditions (concentration of initiators and cofactors) to challenge peroxidation in each preparation under study. On the basis of the PnA assay, Fe2+/ascorbate was selected among the different initiator systems to assess the effect of lipid peroxidation upon biochemical and biophysical parameters of SR membranes. Under mildly controlled conditions at 25 degrees C, the lipid degradative process, as detected by fatty acid analysis, decreases the Ca2+ uptake (up to about 50% of control) and reduces the Ca2+ pump efficiency (Ca2+/ATP ratio) up to about 58% of control, without inactivation the ATPase enzyme turnover. The effect of lipid peroxidation on the SR bilayer organization is dependent either on the extent of lipid peroxidation or on the depth of the bilayer as probed by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene and by intramolecular excimerization of 1,3-di(1-pyrenyl)propane. It is concluded that the effect of mild lipid peroxidation on Ca2+ pump activity is partially exerted through the alteration of physical properties in the lipid phase or lipid-protein interfaces.
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PMID:Lipid peroxidation in sarcoplasmic reticulum membranes: effect on functional and biophysical properties. 838 29

Mitochondria were prepared from three lymphoblast cell lines from patients with high percentage copy numbers of the human mtDNA 8993 mutation and compared to those prepared from related and non-related control cell lines. Rates of ATP synthesis with pyruvate/malate, succinate/rotenone, ascorbate/N'N'N'N' tetramethyl phenylene diamine were reduced to 67%, 58% and 54% of the control rates, respectively. The backward reaction measured as oligomycin sensitive ATPase was reduced to an average of 42% of that in controls. This mutation which changes a conserved leucine to an arginine in the putative membrane proton channel of mitochondrial ATPase effectively reduces the overall rate of oxidative phosphorylation.
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PMID:The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. 847 14

The aim of this study was to evaluate the substrate (ATP) kinetics of erythrocyte membrane Na, K-ATPase in children with borderline or essential hypertension. Although the activity of Na, K-ATPase in the presence of in vivo concentrations of ATP was not significantly altered, kinetic studies showed an obvious inhibition of enzyme activity in the erythrocyte membrane of children with borderline or essential hypertension. Hanes plot analysis revealed a decrease of V(max) from 7.19 in erythrocytes from control subjects to 4.93 and 3.33 in those from children with borderline or essential hypertension, respectively. A mean value of the K(m) decreased from 0.10 in the control to 0.08 and 0.02 in children with borderline or essential hypertension, respectively. The energy status of erythrocytes, estimated by ATP, ADP and AMP levels, ATP/ADP ratio, and adenylate energy charge (AEC) was not significantly changed in the cells from hypertensive children. The use of a free radical-generating system (FeSO4/ascorbate) in vitro significantly reduced enzyme activity in the control erythrocytes while in those from hypertensive children it was abolished completely. The level of lipid peroxides was considerably higher (+ 37 per cent) in the plasma, while that of reduced glutathione was significantly lower both in the erythrocytes and the plasma of children with essential hypertension than in healthy children. These results indicate significant alterations of the antioxidant status which could be the cause of the inhibited Na, K-ATPase activity in erythrocyte membranes from hypertensive children.
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PMID:Alteration of erythrocyte membrane Na, K-ATPase in children with borderline or essential hypertension. 864 Sep 56

Various authors have suggested that nitric oxide (.NO) exerts cytotoxic effects through the inhibition of cellular respiration. Indeed, in intact cells .NO inhibits glutamate-malate (complex I) as well as succinate (complex II)-supported mitochondrial electron transport, without affecting TMPD/ascorbate (complex IV)-dependent respiration. However, experiments in our lab using isolated rat heart mitochondria indicated that authentic .NO inhibited electron transport mostly by reversible binding to the terminal oxidase, cytochrome a3, having a less significant effect on complex II- and no effect on complex I-electron transport components. The inhibitory action of .NO was more profound at lower oxygen tensions and resulted in differential spectra similar to that observed in dithionite-treated mitochondria. On the other hand, continuous fluxes of .NO plus superoxide (O.(2)(-)), which lead to formation of micromolar steady-state levels of peroxynitrite anion (ONOO-), caused a strong inhibition of complex I- and complex II-dependent mitochondrial oxygen consumption and significantly inhibited the activities of succinate dehydrogenase and ATPase, without affecting complex IV-dependent respiration and cytochrome c oxidase activity. In conclusion, even though nitric oxide can directly cause a transient inhibition of electron transport, the inhibition pattern of mitochondrial respiration observed in the presence of peroxynitrite is the one that closely resembles that found secondary to .NO interactions with intact cells and strongly points to peroxynitrite as the ultimate reactive intermediate accounting for nitric oxide-dependent inactivation of electron transport components and ATPase in living cells and tissues.
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PMID:Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. 864 9

Cuprous ions at micromolar concentrations induced swelling of rat liver mitochondria in isotonic solutions of potassium thiocyanate and potassium acetate. The swelling in K-acetate in the presence of the protonophore [corrected] carbonyl cyanide m-chloropenylhydrazone was partly inhibited by glibenclamide. In K(+)-containing media, Cu+ collapsed the mitochondrial membrane potential formed by operation of the respiratory chain with succinate or tetramethyl p-phenylenediamine + ascorbate as substrates or by the proton-pumping ATPase. In contrast, in K(+)-free media, isotonic sucrose or choline chloride, but not in NaC1, Cu+ induced a transient potassium gradient potential. These results indicate that cuprous ions at low concentrations, apart from promoting the electroneutral K+/H+ exchange, facilitate the uniport of K+, presumably by activating the mitochondrial potassium channel sensitive to glibenclamide.
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PMID:Cuprous ions activate glibenclamide-sensitive potassium channel in liver mitochondria. 867 Mar 5


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