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)

In the present work, we studied the effects of phenoxyl radicals, generated by tyrosinase-catalyzed oxidation of a phenolic antitumor drug, Etoposide (VP-16), on a purified dog kidney Na+/K(+)-ATPase by characterizing interactions of VP-16 phenoxyl radicals with the enzyme's SH-groups by ESR and correlating the loss of the enzymatic activity with the oxidation of its SH-groups, and oxidation of VP-16. VP-16/tyrosinase caused inhibition of Na+/K(+)-ATPase which was dependent on the incubation time and concentration of tyrosinase. The inhibition of Na+/K(+)-ATPase was accompanied by a decrease of DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)-titratable SH-groups. In the presence of Na+/K(+)-ATPase, a typical ESR signal of the VP-16 phenoxyl radical could be observed only following a lag period the duration of which was proportional to the concentration of the Na+/K(+)-ATPase added. Our HPLC measurements demonstrated that Na+/K(+)-ATPase protected VP-16 against tyrosinase-catalyzed oxidation. Combined these results suggest that redox-cycling of VP-16/VP-16 phenoxyl radical by SH-groups of Na+/K(+)-ATPase occurred. Ascorbate which is known to reduce the VP-16 phenoxyl radicals, protected the enzyme against inactivation, prevented oxidation of the enzyme's SH-groups. Reduction of VP-16 phenoxyl radicals by ascorbate was directly observed by the semidehydroascorbyl radical signal in the ESR spectra. VP-16 phenoxyl radical-induced oxidation of sulfhydryls and inhibition of the Na+/K(+)-ATPase may be responsible for at least some of its clinical side effects (e.g., cardiotoxicity) which can be prevented by ascorbate.
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PMID:Inhibition of Na+/K(+)-ATPase by phenoxyl radicals of etoposide (VP-16): role of sulfhydryls oxidation. 749 37

Synaptosomes obtained from rat striata lesioned by central injection of endothelin-1 (ET-1) were analyzed for the levels of lipid peroxidation products, the susceptibility to lipid peroxidation, the phospholipid and free fatty acid composition and the activity of Na+,K(+)-ATPase one hour after ET-1 treatment. The intrastriatal injection of ET-1 promoted an increase of endogenous thiobarbituric reactive substances (TBARS), as index of free radical mediated lipid damage, and a greater susceptibility to iron/ascorbate-induced lipid peroxidation. The pattern of free fatty acids showed a significant decrease of arachidonic and docosahexaenoic acid consequent to ET-1 treatment. The analysis of lipid composition showed a significant loss of phospholipids: among phospholipid species, sphingomyelin and phosphatidylethanolamine plasmalogen were particularly reduced by ET-1 treatment. The activity of membrane-bound Na+,K(+)-ATPase was also significantly reduced in synaptosomes obtained from ET-1 lesioned striata. Taken together these results indicate a significant modification of synaptosomal membrane of ET-1 treated rat striata, possibly due to a free radical mediated damage.
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PMID:Effect of endothelin-1 induced ischemia on peroxidative damage and membrane properties in rat striatum synaptosomes. 756 65

It is established that acetaminophen exhibits oxidative behaviour. The effects of acetaminophen (0.3-14.5 microM) on methemoglobin levels, superoxide dismutase and Na(+)-K+ ATPase activities of normal and vitamin E or vitamin C pretreated erythrocytes were investigated. In acetaminophen incubated erythrocytes, methemoglobin concentration and superoxide dismutase activity were increased in a dose and incubation-time dependent manner, the activity of Na(+)-K+ ATPase was decreased by acetaminophen treatment. Vitamin E (1mg/dl of erythrocyte suspension) or vitamin C (1mg/dl of erythrocyte suspension) provided partial protection of hemoglobin, superoxide dismutase and Na(+)-K+ ATPase against acetaminophen action. Vitamin E was more effective than vitamin C.
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PMID:Effects of acetaminophen on methemoglobin, superoxide dismutase and Na(+)-K+ ATPase activities of human erythrocytes. 762 22

The effectiveness of a phenolic antioxidant as a radical scavenger is determined by its reactivity toward peroxyl radicals and also by the reactivity of the anti-oxidant phenoxyl radical toward oxidation substrate. If the phenoxyl radical efficiently interacts with vitally important biomolecules, this interaction may result in oxidative damage rather than antioxidant protection. In the present work, we studied effects of phenoxyl radicals generated from a phenolic antitumor drug, Etoposide (VP-16), on oxidation of thiols and activity of Ca(2+)-ATPase in sarcoplasmic reticulum (SR) membranes from skeletal muscles. We found that VP-16 is an effective scavenger of peroxyl radicals as judged by its ability to inhibit a water-soluble azo-initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH)-induced (i) chemiluminescence (oxidation) of luminol, (ii) fluorescence decay (oxidation) of cis-parinaric acid incorporated in SR membranes, and (iii) peroxidation of SR membrane lipids. VP-16 did not prevent AAPH-induced oxidation of sulfhydryl groups and inhibition of Ca(2+)-ATPase in SR membranes. Electron spin resonance measurements showed that AAPH-induced VP-16 phenoxyl radicals were reduced by interaction with SR thiols. By using tyrosinase to generate VP-16 phenoxyl radicals as the only source of free radicals in the model system, we found that inhibition of Ca(2+)-ATPase was accompanied by oxidation of about 5 mol of Ca(2+)-ATPase SH groups per 1 mol of oxidized VP-16. Secondary products of VP-16 oxidation (including VP-16 o-quinone) were not efficient in inhibiting SR Ca(2+)-ATPase. Reduction of VP-16 phenoxyl radicals by ascorbate protected against AAPH- and tyrosinase-induced thiol oxidation and Ca(2+)-ATPase inhibition. The results suggest that efficient phenolic scavengers of peroxyl radicals such as VP-16--which are commonly considered as potent antioxidants--may themselves produce oxidative stress due to secondary reactions of their phenoxyl radicals with thiols.
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PMID:Antioxidant paradoxes of phenolic compounds: peroxyl radical scavenger and lipid antioxidant, etoposide (VP-16), inhibits sarcoplasmic reticulum Ca(2+)-ATPase via thiol oxidation by its phenoxyl radical. 763 14

The significance of the H(+)-ATPase in iron absorption by rabbit reticulocytes is explored using isolated endosomes, effects of inhibitors, and the purified proton pump. We have recently reported H(+)-ATPase-mediated iron transfer across a liposomal membrane (Li et al., 1994). In this report, the effect of H(+)-ATPase inhibitors on iron mobilization is investigated at pH 6.0 in the presence of 15 microM FCCP in order to dissociate 59Fe(III) from transferrin and eliminate the kinetic effects of acidification by the ATPase. Iron transport by isolated endosomes is decreased 50% by the cation pore inhibitor dicyclohexylcarbodiimide (DCCD) for ascorbate-mediated iron mobilization and increased by 40-50% when NADH and ferrocyanide are used as electron donors. In contrast, the ATPase hydrolysis inhibitors N-methylmaleimide (NEM) and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD) increase iron mobilization when NADH and ferrocyanide are used as reductants but have negligible effects for ascorbate. The differential inhibition or enhancement by DCCD, NEM, and NBD with respect to the reductants used for mobilization indicates that the H(+)-ATPase may be involved in the multiple pathways or iron transport found in isolated rabbit reticulocyte endosomes. Effects of inhibitors of ATP hydrolysis suggest significant structural interactions between the proton pump and sites for iron binding and/or reduction. The isolated H(+)-ATPase binds iron as revealed by using nondenaturing electrophoretic and chromatographic methods. One class of iron binding sites is suggested to be the 17.5 kDa proton pore subunits of the H(+)-ATPase which also covalently react with DCCD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Iron binding, a new function for the reticulocyte endosome H(+)-ATPase. 771 Oct 32

Among aging disabilities, the one associated with the progressive decline of vision is functionally most disadvantageous. Cataracts are one of the more common causes of such visual disability. Several predisposing factors have been identified in the genesis of this disease. While it is perhaps a multifactorial process, significant developments have taken place in recent years suggesting that oxygen radicals are involved in the development of this aging manifestation. Antioxidant enzymes, such as catalase and superoxide dismutase, have been demonstrated to protect the lens cell membrane from oxidative stress as reflected by the prevention of the Na(+)-K(+)-ATPase-dependent pump deterioration due to oxyradical-dependent oxidation of its proteins and lipids. From the nutritional point of view, antioxidants such as ascorbate and vitamin E also offer significant protection to the lens against damage due to oxidative stress. Evidence regarding the protective effect of these nutrients has been based on lens organ culture studies in the presence of active oxygen, generated photochemically as well as enzymatically. The experiment involving photochemical environs simulate the status of the eye during the photopic vision. In vivo, the effectiveness of ascorbate against cataracts has been tested in rat pups developing cataracts under the oxidative influence of sodium selenite. Certain antioxidants produced metabolically also may be useful in protecting against cataracts. Pyruvate produced in glucose metabolism seems to be an important antioxidant. The efficacy of this compound has been tested within in vitro organ culture as well as in vivo, the latter experiments being done with selenite-treated rats. There is a hope that these and other nutritional and metabolic antioxidants may one day be useful in delaying or even preventing cataract formation in human beings.
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PMID:Prevention of cataracts by nutritional and metabolic antioxidants. 774 71

Ozone (5 mumol.min-1) inhibited the human erythrocyte membrane Na(+)-K+ ATPase (EC.3.6.1.39) activity in a time dependent manner. Inhibition was more pronounced for the first 5 min of ozone exposure in the directly ozone exposed membranes than in the membranes prepared from ozone exposed erythrocytes. However, Na(+)-K+ ATPase activities of both preparations were inhibited to the same extent (about 70%) at the end of 10 min ozone exposure. It was also determined that there was a close relationship between the decrease of enzyme activity and the increase in the thiobarbituric acid reactive substances in both types of preparations. Na(+)-K+ ATPase was inhibited by ozone even at the presence of vitamin E or vitamin C. However, the degree of the inhibitions and the amounts of thiobarbituric acid reactive products formed were smaller than the corresponding values found in the absence of these vitamins.
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PMID:Effects of ozone on the activity of erythrocyte membrane Na(+)-K+ ATPase. 780 27

Certain peptide drugs, such as the linear hydrophobic renin-inhibitor EMD 51921, are rapidly eliminated via the bile. At the sinosoidal membrane of liver cells EMD 51921 is taken up via a sodium-independent carrier-mediated mechanism, competing for the uptake of bile acids. Until now, the mechanisms of biliary excretion of EMD 51921 were unknown. In this study we describe an ATP-dependent transport system for the enzymatically and metabolically stable hydrophobic linear renin-inhibiting peptide EMD 51921. The ATP-dependent uptake into the osmotic reactive intravesicular space is saturable (Km 12 microM, Vmax 663 pmol/min per mg protein), temperature dependent and specifically requires ATP. Transport is inhibited by vanadate but not by ouabain, EGTA or NaN3, and does not function in basolateral plasma membrane vesicles. Transport is not altered in canalicular membrane vesicles isolated from Tr- rats lacking the canalicular ATP-dependent transport of cysteinyl leukotrienes and related anions. Transport is inhibited by taurocholate, a typical substrate of the canalicular ATP-dependent bile acid transporter, but also by vincristine and daunomycin, substrates of P-glycoproteins. EMD 51921, however, only inhibits the uptake of taurocholate, whereas the transport of daunomycin is not influenced. Taurocholate and EMD 51921 are mutually non- or un-competitive transport inhibitors. Incubation of rat liver canalicular membranes with micromolar concentrations of EMD 51921 resulted in a 1.8-2.5-fold increase in the rate of ATP-hydrolysis. In contrast, ATP-hydrolysis was not affected by fragments of the peptide that are not transported in an ATP-dependent manner. The apparent Km value (EMD) for ATP-hydrolysis is 68 microM. Vmax is 0.032 U/mg protein. ATPase activity is pH dependent. Stimulation of ATP-hydrolysis is inhibited by vanadate, NEM, hydroxymercuribenzoate and ascorbate, but is not affected by ouabain, EGTA or NaN3. EMD 51921 does not stimulate the ATPase activity of the Na+/K(+)-ATPase isolated from kidney medulla. The EMD-stimulatable ATPase seems to be distinct from the glutathione-S-conjugate stimulatable ATPase and the mdr 1a/b gene products and differs in its characteristics from that of the canalicular ecto-ATPase.
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PMID:ATP-dependent transport of the linear renin-inhibiting peptide EMD 51921 by canalicular plasma membrane vesicles of rat liver: evidence of drug-stimulatable ATP-hydrolysis. 784 Nov 85

A variety of events, including inhalation of atmospheric chemicals, trauma, and ischemia-reperfusion, may cause generation of reactive oxygen species in the lung and result in airways constriction. The specific metabolic mechanisms that translate oxygen radical production into airways constriction are yet to be identified. In the lung, calcium homeostasis is central to release of bronchoactive and vasoactive chemical mediators and to regulation of smooth muscle cell contractility, i.e., airway constriction. In the present work, we characterized Ca(2+)-transport in the microsomal fraction of mouse lungs, and determined how reactive oxygen species, generated by Fe2+/ascorbate and H2O2/hemoglobin, affected Ca2+ transport. The microsomal fraction of pulmonary tissue accumulated 90 +/- 5 nmol Ca2+/mg protein by an ATP-dependent process in the presence of 15 mM oxalate, and 16 +/- 2 nmol Ca2+ in its absence. In the presence of oxalate, the rate of Ca2+ uptake was 50 +/- 5 nmol Ca2+/min per mg protein at pCa 5.9 (37 degrees C). The Ca(2+)-ATPase activity was 50-60 nmol Pi/min per mg protein (pCa 5.9, 37 degrees C) in the presence of alamethicin. Inhibitors of mitochondrial H(+)-ATPase had no effect on the Ca2+ transport. Half-maximal activation of Ca2+ transport was produced by 0.4-0.5 microM Ca2+. Endoplasmic reticulum Ca(2+)-pump (SERC-ATPase) was found to be predominantly responsible for the Ca(2+)-accumulating capacity of the pulmonary microsomes. Incubation of the microsomes in the presence of either Fe2+/ascorbate or H2O2/hemoglobin resulted in a time-dependent accumulation of peroxidation products (TBARS) and in inhibition of the Ca2+ transport. The inhibitory effect of Fe2+/ascorbate on Ca2+ transport strictly correlated with the inhibition of the Ca(2+)-ATPase activity. These results are the first to indicate a highly active microsomal Ca2+ transport system in murine lungs which is sensitive to endogenous oxidation products. The importance of this system to pulmonary disorders exacerbated by oxidative chemicals remains to be studied.
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PMID:Pulmonary microsomes contain a Ca(2+)-transport system sensitive to oxidative stress. 789 26

1. Heavy metals (Hg2+, Cu2+, Cd2+, Zn2+, Pb2+) at micromolar concentrations strongly inhibit the Ca(2+)-ATPase activity present in the plasma-membrane obtained from the gill cells of Mytilus galloprovincialis Lam. Heavy metals act through inhibition of the formation of the phosphorylated intermediate. 2. All the heavy metals tested inhibit the Ca(2+)-ATPase activity, the effect following the order: Hg2+ > Pb2+ > Cu2+ > Cd2+ > Zn2+; the simultaneous addition of different heavy metals causes a summatory inhibition of the enzyme activity; addition to the reaction mixture of GSH at a final concentration of 0.5 mM, reverses inhibitory effects of heavy metals. 3. The inhibitory effects of Cu2+ on Ca(2+)-ATPase are highly enhanced by addition of ascorbate to the reaction mixture. In the presence of ascorbate (100 microM), copper strongly stimulates the lipid peroxidation damage of the gill plasma-membranes, a result that may explain the high copper cytotoxicity.
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PMID:Effects of heavy metals on the Ca(2+)-ATPase activity present in gill cell plasma-membrane of mussels (Mytilus galloprovincialis Lam.). 790 5


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