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)

Extracellular superoxide dismutase (EC-SOD) contributes only a small fraction to total SOD activity in the heart but is strategically located to scavenge free radicals in the extracellular compartment. EC-SOD expression is decreased in myocardial-infarction (MI)-induced heart failure, but whether EC-SOD can abrogate oxidative stress or modify MI-induced ventricular remodeling has not been previously studied. Consequently, the effects of EC-SOD gene deficiency (EC-SOD KO) on left ventricular (LV) oxidative stress, hypertrophy, and fibrosis were studied in EC-SOD KO and wild-type mice under control conditions, and at 4 and 8 weeks after permanent coronary artery ligation. EC-SOD KO had no detectable effect on LV function in normal hearts but caused small but significant increases of LV fibrosis. At 8 weeks after MI, EC-SOD KO mice developed significantly more LV hypertrophy (LV mass increased 1.64-fold in KO mice compared to 1.35-fold in wild-type mice; p<0.01) and more fibrosis and myocyte hypertrophy which was more prominent in the peri-infarct region than in the remote myocardium. EC-SOD KO mice had greater increases of nitrotyrosine in the peri-infarct myocardium, and this was associated with a greater reduction of LV ejection fraction, a greater decrease of sarcoplasmic or endoplasmic reticulum calcium2+ ATPase, and a greater increase of atrial natriuretic peptide in the peri-infarct zone compared to wild-type mice. EC-SOD KO was associated with more increases of phosphorylated p38 (p-p38(Thr180/Tyr182)), p42/44 extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and c-Jun N-terminal kinase (p-JNK(Thr183/Tyr185)) both under control conditions and after MI, indicating that EC-SOD KO increases activation of mitogen-activated protein kinase signaling pathways. These findings demonstrate that EC-SOD plays an important role in protecting the heart against oxidative stress and infarction-induced ventricular hypertrophy.
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PMID:Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction. 1820 58

The membrane-embedded K (+)-translocating KdpFABC complex from Escherichia coli belongs to the superfamily of P-type ATPases, which share common structural features as well as a well-studied catalytic mechanism. However, little is known about the oligomeric state of this class of enzymes. For many P-type ATPases, such as the Na (+)/K (+)-ATPase, Ca (2+)-ATPase, or H (+)-ATPase, an oligomeric state has been shown or is at least discussed but has not yet been characterized in detail. In the KdpFABC complex, kinetic analyses already indicated the presence of two cooperative ATP-binding sides within the functional enzyme and, thus, also point in the direction of a functional oligomer. However, the nature of this oligomeric state has not yet been fully elucidated. In the present work, a close vicinity of two KdpB subunits within the functional KdpFABC complex could be demonstrated by chemical cross-linking of native cysteine residues using copper 1,10-phenanthroline. The cysteines responsible for cross-link formation were identified by mutagenesis. Cross-linked and non-cross-linked KdpFABC complexes eluted with the same apparent molecular weight during gel filtration, which corresponded to the molecular weight of a homodimer, thereby clearly indicating that the KdpFABC complex was purified as a dimer. Isolated KdpFABC complexes were analyzed by transmission electron microscopy and exhibited an approximately 1:1 distribution of mono- and dimeric particles. Finally, reconstituted functional KdpFABC complexes were site-directedly labeled with flourescent dyes, and intermolecular single-molecule FRET analysis was carried out, from which a dissociation constant for a monomer/dimer equilibrium between 30 and 50 nM could be derived.
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PMID:K+-translocating KdpFABC P-type ATPase from Escherichia coli acts as a functional and structural dimer. 1829 81

Fluorescence microscopic observation of individual T4 DNA molecules revealed that the MukBEF complex (bacterial condensin) and its subunit, the MukB (a member of the SMC [structural maintenance of chromosomes] superfamily) homodimer, of Escherichia coli markedly shrunk large DNA molecules in the presence of hydrolyzable ATP. In contrast, in the presence of ADP or ATP-gammaS, the conformation of DNA was almost not changed. This suggests that the ATPase activity of subunit MukB is essential for shrinking large DNA molecules. Stretching experiments on the shrunken DNA molecules in the presence of ATP and MukBEF indicated a cross-bridging interaction between DNA molecules.
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PMID:ATP-induced shrinkage of DNA with MukB protein and the MukBEF complex of Escherichia coli. 1832 68

As one of the major genes encoding plasma membrane H+ -ATPase, AHA1 gene plays an important role in regulating plant development and resistance to adverse stress. Taking AHA1 transgenic and wild type Arabidopsis thaliana as test plants, the nutrient uptake, resistance to oxidative stress, and organic acid secretion of the plants under aluminum (Al) stress were examined. The results showed that Al decreased the uptake of nitrogen (N), potassium (K), calcium (Ca) and magnesium (Mg), but increased the phosphorus (P) uptake by A. thaliana roots. AHA1 transgenic plant could accumulate more P and less Al than wild type plant. Al stress induced the increase of plant SOD and POD activities, but no significant difference was observed between AHA1 transgenic and wild type A. thaliana. Al triggered the secretion of organic acids significantly, and AHA1 transgenic plant secreted more organic acids than wild type plant. Vanadate, an inhibitor of plasma membrane H+ -ATPase, could inhibit the secretion of organic acids significantly, while Zn2+ and Mg2+ could promote the Al-induced secretion, and partially improve the inhibitory effects triggered by vanadate. It was suggested that AHA1 transgenic A. thaliana could increase its Al resistance via enhanced P uptake and organic acid secretion.
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PMID:[Aluminum-resistance of AHA1 transgenic Arabidopsis thaliana: physiological analysis]. 1865 3

A single molecule of the motor enzyme kinesin-1 keeps a tight grip on its microtubule track, making tens or hundreds of discrete, unidirectional 8 nm steps before dissociating. This high duty ratio processive movement is thought to require a mechanism in which alternating stepping of the two head domains of the kinesin dimer is driven by alternating, overlapped cycles of ATP hydrolysis by the two heads. The R210K point mutation in Drosophila kinesin heavy chain was reported to disrupt the ability of the enzyme active site to catalyze ATP P-O bond cleavage. We expressed R210K homodimers as well as isolated R210K heads and confirmed that both are essentially inactive. We then coexpressed tagged R210K subunits with untagged wild-type subunits and affinity purified R210K/wild-type heterodimers together with the inactive R210K homodimers. In contrast to the R210K head or homodimer, the heterodimer was a highly active (>50% of wild-type) microtubule-stimulated ATPase, and the heterodimer displayed high duty ratio processive movement in single-molecule motility experiments. Thus, dimerization of a subunit containing the inactivating mutation with a functional subunit can complement the mutation; this must occur either by lowering or by bypassing kinetic barriers in the ATPase or mechanical cycles of the mutant head. The observations provide support for kinesin-1 gating mechanisms in which one head stimulates the rate of essential processes in the other.
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PMID:Processive movement by a kinesin heterodimer with an inactivating mutation in one head. 1870 29

The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNK(mut)) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK(mut) mice. These effects in MNK(mut) mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNK(mut) mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK(mut) mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.
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PMID:Role of Menkes ATPase in angiotensin II-induced hypertension: a key modulator for extracellular superoxide dismutase function. 1876 96

Aluminium (Al) is the most abundant metal known for its neurotoxicity in humans. It gains easy access to the central nervous system under normal physiological conditions and accumulates in different brain regions. It has been reported to be involved in the etiology of several neurodegenerative diseases. In this study, we have investigated the effects of long-term intake of aluminium chloride (AlCl(3)) on the electrophysiological, behavioral, biochemical and histochemical functions of hippocampus. Wistar rats were fed with AlCl(3) at a dose of 50mg/(kgday) for 6 months in the drinking water. Effect of long-term intake of Al was studied on the electrical activity of hippocampal CA1 and CA3 regions in brain of young and old rats. Morris water maze and open field tests were performed to investigate the cognitive and anxiety status of aging rats intoxicated with aluminium. Our studies indicate that aluminium intake results in increased multiple unit activity and adversely affect the spatial learning and memory abilities of both young and old rats. Aluminium intake also inflicts oxidative stress-related damage to lipids, membrane associated proteins (Na-K ATPase and PKC) and endogenous antioxidant enzyme activity (SOD, GPx and GST). The compromised antioxidant system might be playing a crucial role in the observed Al-induced alterations. We have observed that the magnitude of AlCl(3)-induced alteration was considerably higher in younger group of rats compared to older group. In conclusion, the results of the present study implicates that aluminium treatment exerts its neurotoxic effects by altering the overall physiology of brain, and the induced changes were strongly correlated with each other.
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PMID:Aluminium-induced electrophysiological, biochemical and cognitive modifications in the hippocampus of aging rats. 1881 12

P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, has been implicated in multidrug resistance of several cancers as a result of its overexpression. In this work, rationally designed second-generation P-gp inhibitors are disclosed, based on dimerized versions of the substrates quinine and quinidine. These dimeric agents include reversible tethers with a built-in clearance mechanism. The designed agents were potent inhibitors of rhodamine 123 efflux in cultured cancer cell lines that display high levels of P-gp expression at the cell surface and in transfected cells expressing P-gp. The quinine homodimer Q2, which was tethered by reversible ester bonds, was particularly potent (IC(50) approximately 1.7 microM). Further studies revealed that Q2 inhibited the efflux of a range of fluorescent substrates (rhodamine 123, doxorubicin, mitoxantrone, and BODIPY-FL-prazosin) from MCF-7/DX1 cells. The reversibility of the tether was confirmed in experiments showing that Q2 was readily hydrolyzed by esterases in vitro (t(1/2) approximately 20 h) while demonstrating high resistance to nonenzymatic hydrolysis in cell culture media (t(1/2) approximately 21 days). Specific inhibition of [(125)I]iodoarylazidoprazosin binding to P-gp by Q2 verified that the bivalent agent interacted specifically with the drug binding site(s) of P-gp. Q2 was also an inhibitor of verapamil-stimulated ATPase activity. In addition, low concentrations of Q2 stimulated basal P-gp ATPase levels. Finally, Q2 was shown to inhibit the transport of radiolabeled paclitaxel (Taxol) in MCF-7/DX1 cells, and it completely reversed the P-gp-mediated paclitaxel resistance phenotype.
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PMID:Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers. 1894 21

The water-water cycle is the electron flow through scavenging enzymes for the reactive species of oxygen in chloroplasts, and is proposed to play a role in alternative electron sink in photosynthesis. Here we showed that the water-water cycle is impaired in the T-DNA insertion mutant of AtHMA1 gene encoding a Cu transporting ATPase in chloroplasts. Chlorophyll fluorescence under steady state was not affected in hma1, indicating that photosynthetic electron transport under normal condition was not impaired. Under electron acceptor limited conditions, however, hma1 showed distinguished phenotype in chlorophyll fluorescence characteristics. The most severe phenotype of hma1 could be observed in high (0.1%) CO(2) concentrations, indicating that hma1 has the defect other than photorespiration. The transient increase of chlorophyll fluorescence upon the cessation of the actinic light as well as the NPQ induction of chlorophyll fluorescence revealed that the two pathways of cyclic electron flow around PSI, NDH-pathway and FQR-pathway, are both intact in hma1. Based on the NPQ induction under 0% oxygen condition, we conclude that the water-water cycle is impaired in hma1, presumably due to the decreased level of Cu/Zn SOD in the mutant. Under high CO(2) condition, hma1 exhibited slightly higher NPQ induction than wild type plants, while this increase of NPQ in hma1 was suppressed when hma1 was crossed with crr2 having a defect in NDH-mediated PSI cyclic electron flow. We propose that the water-water cycle and NDH-mediated pathways might be regulated compensationally with each other especially when photorespiration is suppressed.
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PMID:A T-DNA insertion mutant of AtHMA1 gene encoding a Cu transporting ATPase in Arabidopsis thaliana has a defect in the water-water cycle of photosynthesis. 1914 36

Overexposure to cadmium (Cd) can induce kidney damage, which was related to the oxidative damage and disturb intracellular Ca2+ homeostasis. Chlorpromazine (CPZ), targeting calmodulin (CaM), and the Ca2+ channel blocker Verapamil (Ver) are involved in intracellular Ca2+ homeostasis processes. The aim of the study was to investigate the kidney damage caused by Cd administrated for 6 weeks and to evaluate the effects of pre-treatment with either chlorpromazine or verapamil on Cd-induced kidney damage. Thirty-two Wistar rats were divided randomly into 4 groups by weight, i.e., control group, Cd-treated group, and CPZ or Ver pre-treated group. The Cd-treated group rats were subcutaneously (s.c.) injected with 7micromol CdCl2/kg body weight/day. The CPZ and Ver pre-treated group rats were intraperitoneally (i.p.) injected with 5mg CPZ/kg body weight/day, 4mg Ver/kg body weight/day, respectively, 1h before the s.c. administration of 7micromol CdCl2/kg body weight/day. The control group rats were injected s.c. with saline at the same time. The volume of injection was 2ml/kg body weight, 5 times per week, for up to 6 weeks. After 6 weeks, Cd concentrations in the renal cortex and urine were significantly higher in Cd-treated group than that in controls. Cd concentrations of the urine in CPZ and Ver pre-treated groups were significantly lower than that in Cd-treated group, but there were no significant changes in the renal cortex. Compared with the controls, urinary NAG, ALP activities, and the levels of GSH, MDA, and the activities of PKC, Na(+)-K(+)-ATPase, and Ca(2+)-ATPase in rats from the Cd-treated group were significantly increased. SOD activity was suppressed by Cd. Urinary NAG activity and the level of GSH and the activities of PKC and Ca(2+)-ATPase in both CPZ and Ver pre-treated groups were significantly lower than that in Cd-treated rats. The present results showed that Cd-induced kidney damage was related to the oxidative damage and disturb intracellular Ca2+ homeostasis. Both CPZ and Ver possess some ability to prevent cadmium-induced kidney damage via antioxidative action and by maintaining calcium homeostasis.
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PMID:Protective effects of Chlorpromazine and Verapamil against cadmium-induced kidney damage in vivo. 1918 51


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