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)

Histatin 5 (Hst5) is a human salivary antimicrobial peptide that targets fungal mitochondria. In the human parasitic protozoa Leishmania, the mitochondrial ATP production is essential, as it lacks the bioenergetic switch between glycolysis and oxidative phosphorylation described in some yeasts. On these premises, Hst5 activity was assayed on both stages of its life cycle, promastigotes and amastigotes (LC(50)=7.3 and 14.4 microM, respectively). In a further step, its lethal mechanism was studied. The main conclusions drawn were as follows: 1) Hst5 causes limited and temporary damage to the plasma membrane of the parasites, as assessed by electron microscopy, depolarization, and entrance of the vital dye SYTOX Green; 2) Hst5 translocates into the cytoplasm of Leishmania in an achiral receptor-independent manner with accumulation into the mitochondrion, as shown by confocal microscopy; and 3) Hst5 produces a bioenergetic collapse of the parasite, caused essentially by the decrease of mitochondrial ATP synthesis through inhibition of F(1)F(0)-ATPase, with subsequent fast ATP exhaustion. By using the Hst5 enantiomer, it was found that the key steps of its lethal mechanism involved no chiral recognition. Hst5 thus constitutes the first leishmanicidal peptide with a defined nonstereospecific intracellular target. The prospects of its development, by its own or as a carrier molecule for other leishmanicidal molecules, into a novel anti-Leishmania drug with a preferential subcellular accumulation are discussed.
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PMID:Human antimicrobial peptide histatin 5 is a cell-penetrating peptide targeting mitochondrial ATP synthesis in Leishmania. 1823 Jun 84

Methylmalonic acidemias consist of a group of inherited neurometabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity clinically and biochemically characterized by neurological dysfunction, methylmalonic acid (MMA) accumulation, mitochondrial failure and increased reactive species production. Although previous studies have suggested that nitric oxide (NO) plays a role in the neurotoxicity of MMA, the involvement of NO-induced nitrosative damage from inducible nitric oxide synthase (iNOS) in MMA-induced seizures are poorly understood. In the present study, we showed a decrease of time spent convulsing induced by intracerebroventricular administration of MMA (2 micromol/2 microL; i.c.v.) in iNOS knockout (iNOS(-/-)) mice when compared with wild-type (iNOS(+/+)) littermates. Visual analysis of electroencephalographic recordings (EEG) showed that MMA injection induced the appearance of high-voltage synchronic spike activity in the ipsilateral cortex which spreads to the contralateral cortex while quantitative electroencephalographic analysis showed larger wave amplitude during MMA-induced seizures in wild-type mice when compared with iNOS knockout mice. We also report that administration of MMA increases NOx (NO(2) plus NO(3) content) and 3-nitrotyrosine (3-NT) levels in a greater extend in iNOS(+/+) mice than in iNOS(-/-) mice, indicating that NO overproduction and NO-mediated damage to proteins are attenuated in iNOS knockout mice. In addition, the MMA-induced decrease in Na(+), K(+)-ATPase activity, but not in succinate dehydrogenase (SDH) activity, was less pronounced in iNOS(-/-) when compared with iNOS(+/+) mice. These results reinforce the assumption that metabolic collapse contributes for the secondary toxicity elicited by MMA and suggest that oxidative attack by NO derived from iNOS on selected target such as Na(+), K(+)-ATPase enzyme might represent an important role in this excitotoxicity induced by MMA. Therefore, these results may be of value in understating the pathophysiology of the neurological features observed in patients with methylmalonic acidemia and in the development of new strategies for treatment of these patients.
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PMID:Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice. 1907 47

The apicomplexan parasite Toxoplasma gondii expresses type II NADH dehydrogenases (NDH2s) instead of canonical complex I at the inner mitochondrial membrane. These non-proton-pumping enzymes are considered to be promising drug targets due to their absence in mammalian cells. We recently showed by inhibition kinetics that T. gondii NDH2-I is a target of the quinolone-like compound 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ), which inhibits T. gondii replication in the nanomolar range. In this study, the cationic fluorescent probes Mitotracker and DiOC(6)(3) (3,3'-dihexyloxacarbocyanine iodine) were used to monitor the influence of HDQ on the mitochondrial inner membrane potential (Delta Psi m) in T. gondii. Real-time imaging revealed that nanomolar HDQ concentrations led to a Delta Psi m collapse within minutes, which is followed by severe ATP depletions of 30% after 1 h and 70% after 24 h. Delta Psi m depolarization was attenuated when substrates for other dehydrogenases that can donate electrons to ubiquinone were added to digitonin-permeabilized cells or when infected cultures were treated with the F(o)-ATPase inhibitor oligomycin. A prolonged treatment with sublethal concentrations of HDQ induced differentiation into bradyzoites. This dormant stage is likely to be less dependent on the Delta Psi m, since Delta Psi m-positive parasites were found at a significantly lower frequency in alkaline-pH-induced bradyzoites than in tachyzoites. Together, our studies reveal that oxidative phosphorylation is essential for maintaining the ATP level in the fast-growing tachyzoite stage and that HDQ interferes with this pathway by inhibiting the electron transport chain at the level of ubiquinone reduction.
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PMID:Type II NADH dehydrogenase inhibitor 1-hydroxy-2-dodecyl-4(1H)quinolone leads to collapse of mitochondrial inner-membrane potential and ATP depletion in Toxoplasma gondii. 1928 86

Na,K-ATPase is a ubiquitous transmembrane protein that regulates and maintains the intracellular Na(+) and K(+) gradient necessary for cell homeostasis. Recently, the importance of this pump in external stimuli-induced leukemia cell apoptosis has been increasingly appreciated, however, the exact role of Na,K-ATPase in mitochondrial apoptotic pathway still remains little understood. In this study, we found mitochondrial toxin rotenone caused a rapid mitochondrial membrane potential (MMP) collapse in Jurkat cells followed by plasma membrane depolarization (PMP). Similar results were also obtained in human U937 cells and non-cancerous mouse primary T cells. Rotenone-induced PMP depolarization occurred before apoptosis and well correlated with Na,K-ATPase impairment. To understand the mechanisms, Jurkat cells with mtDNA depletion and catalase overexpression were used. The results demonstrated that both PMP depolarization and Na,K-ATPase impairment induced by rotenone were regulated by mitochondrial H(2)O(2) and Bcl-2. Finally, Na,K-ATPase suppression by ouabain greatly accelerated and enhanced mitochondrial toxins-induced cells apoptosis in Jurkat, U937 and primary T cells. In sum, by using leukemia cells and mouse primary T cells, we confirmed that mitochondria-to-Na,K-ATPase and PMP depolarization might represent a novel mechanism for mitochondria to amplify death signals in the initiation stage of cells apoptosis induced by mitochondrial toxins.
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PMID:Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. 1944 64

During the pre-hibernation season, arctic ground squirrels (AGS) can tolerate 8 min of asphyxial cardiac arrest (CA) without detectable brain pathology. Better understanding of the mechanisms regulating innate ischemia tolerance in AGS has the potential to facilitate the development of novel prophylactic agents to induce ischemic tolerance in patients at risk of stroke or CA. We hypothesized that neuroprotection in AGS involves robust maintenance of ion homeostasis similar to anoxia-tolerant turtles. Ion homeostasis was assessed by monitoring ischemic depolarization (ID) in cerebral cortex during CA in vivo and during oxygen glucose deprivation in vitro in acutely prepared hippocampal slices. In both models, the onset of ID was significantly delayed in AGS compared with rats. The epsilon protein kinase C (epsilonPKC) is a key mediator of neuroprotection and inhibits both Na+/K+-ATPase and voltage-gated sodium channels, primary mediators of the collapse of ion homeostasis during ischemia. The selective peptide inhibitor of epsilonPKC (epsilonV1-2) shortened the time to ID in brain slices from AGS but not in rats despite evidence that epsilonV1-2 decreased activation of epsilonPKC in brain slices from both rats and AGS. These results support the hypothesis that epsilonPKC activation delays the collapse of ion homeostasis during ischemia in AGS.
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PMID:Protein kinase C epsilon activation delays neuronal depolarization during cardiac arrest in the euthermic arctic ground squirrel. 1949 68

SMARCAL1 (also known as HARP) is a SWI/SNF family protein with an ATPase activity stimulated by DNA containing both single-stranded and double-stranded regions. Mutations in SMARCAL1 are associated with the disease Schimke immuno-osseous dysplasia, a multisystem autosomal recessive disorder characterized by T cell immunodeficiency, growth inhibition, and renal dysfunction. The cellular function of SMARCAL1, however, is unknown. Here, using Xenopus egg extracts and mass spectrometry, we identify SMARCAL1 as a protein recruited to double-stranded DNA breaks. SMARCAL1 binds to double-stranded breaks and stalled replication forks in both egg extract and human cells, specifically colocalizing with the single-stranded DNA binding factor RPA. In addition, SMARCAL1 interacts physically with RPA independently of DNA. SMARCAL1 is phosphorylated in a caffeine-sensitive manner in response to double-stranded breaks and stalled replication forks. It has been suggested that stalled forks can be stabilized by a mechanism involving caffeine-sensitive kinases, or they collapse and subsequently recruit Rad51 to promote homologous recombination repair. We show that depletion of SMARCAL1 from U2OS cells leads to increased frequency of RAD51 foci upon generation of stalled replication forks, indicating that fork breakdown is more prevalent in the absence of SMARCAL1. We propose that SMARCAL1 is a novel DNA damage-binding protein involved in replication fork stabilization.
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PMID:Identification of SMARCAL1 as a component of the DNA damage response. 1984 79

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent disorder that is characterized by recurrent sleep-induced collapse of the upper airway. Genioglossus is an important pharyngeal dilator muscle that helps to maintain the patency of the upper airway. The effect of female hormones on pharyngeal dilator muscle activity may be one possible explanation for the differences observed in the prevalence of OSAHS between genders. The aim of this research was to investigate the influence of estrogen on genioglossus activity in rats exposed to chronic intermittent hypoxia (CIH). Eight-wk-old female rats were ovariectomized or sham-operated, received 5-wk of estrogen replacement therapy, and/or were exposed to CIH. The contractile properties of the genioglossus were measured. ATPase staining was performed to determine the per cent fiber-type distribution and to measure the cross-sectional area (CSA) of muscle fibers. Myosin heavy chain phenotypes were determined by gel electrophoresis. Chronic intermittent hypoxia reduced the contractile properties of the genioglossus muscle, decreased the CSA of type IIA fibers, and decreased the proportion of myosin heavy chain IIA, and ovariectomy exacerbated this effect. However, estrogen replacement can partially reverse the effect of CIH in ovariectomized rats. It is concluded that a low female hormone level and CIH may increase fatigue and alter genioglossus structure and function, and may compromise the maintenance of upper airway patency, while estrogen may help to reverse this effect.
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PMID:Effects of estrogen on genioglossal muscle contractile properties and fiber-type distribution in chronic intermittent hypoxia rats. 2012 31

Glucose, in the absence of additional nutrients, induces programmed cell death in yeast. This phenomenon is independent of yeast metacaspase (Mca1/Yca1) and of calcineurin, requires ROS production and it is concomitant with loss of cellular K(+) and vacuolar collapse. K(+) is a key nutrient protecting the cells and this effect depends on the Trk1 uptake system and is associated with reduced ROS production. Mutants with decreased activity of plasma membrane H(+)-ATPase are more tolerant to glucose-induced cell death and exhibit less ROS production. A triple mutant ena1-4 tok1 nha1, devoid of K(+) efflux systems, is more tolerant to both glucose- and H(2)O(2)-induced cell death. We hypothesize that ROS production, activated by glucose and H(+)-ATPase and inhibited by K(+) uptake, triggers leakage of K(+), a process favoured by K(+) efflux systems. Loss of cytosolic K(+) probably causes osmotic lysis of vacuoles. The nature of the ROS-producing system sensitive to K(+) and H(+) transport is unknown.
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PMID:The role of K(+) and H(+) transport systems during glucose- and H(2)O(2)-induced cell death in Saccharomyces cerevisiae. 2021 54

Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide, which reacts with proteins, lipids, and DNA, and promotes cytotoxic and proinflammatory responses. Here, we overview the role of peroxynitrite in various forms of circulatory shock. Immunohistochemical and biochemical evidences demonstrate the production of peroxynitrite in various experimental models of endotoxic and hemorrhagic shock both in rodents and in large animals. In addition, biological markers of peroxynitrite have been identified in human tissues after circulatory shock. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATPase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) polymerase, which promotes cellular energetic collapse and cellular necrosis. Additional actions of peroxynitrite that contribute to the pathogenesis of shock include inactivation of catecholamines and catecholamine receptors (leading to vascular failure) and endothelial and epithelial injury (leading to endothelial and epithelial hyperpermeability and barrier dysfunction), as well as myocyte injury (contributing to loss of cardiac contractile function). Neutralization of peroxynitrite with potent peroxynitrite decomposition catalysts provides cytoprotective and beneficial effects in rodent and large-animal models of circulatory shock.
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PMID:Pathophysiological roles of peroxynitrite in circulatory shock. 2052 70

The Golgi apparatus (GA) is an intracellular organelle that plays a central role in lipid and protein posttranslational modification and sorting. In addition, the GA has been also shown to be involved in Ca(2+) signalling, as: (i) it accumulates Ca(2+) within its lumen in an ATP-dependent process catalyzed by two enzymes, the sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) and the secretory pathway Ca(2+) ATPase1 (SPCA1), and (ii) it releases Ca(2+) during cell stimulation in response to inositol 1,4,5-trisphosphate (IP(3)) receptor activation. Therefore, on this aspect, the GA appears to behave similarly to the major intracellular Ca(2+) store, the endoplasmic reticulum (ER). By using a new FRET-based Ca(2+) probe, specifically targeted to the trans-compartment of the GA, we demonstrate that the organelle is heterogeneous in terms of Ca(2+) handling, the trans-Golgi being insensitive to IP(3) and capable of accumulating Ca(2+) solely through the activity of SPCA1. The SERCA and the IP(3) receptor appear to be restricted to the cis- and intermediate GA compartments. Moreover, selective reduction of Ca(2+) concentration within the trans-Golgi, obtained by reducing the level of SPCA1 by RNAi, results in major alterations of protein trafficking within the secretory pathway and induces the collapse of the entire GA morphology.
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PMID:The trans-golgi compartment: A new distinct intracellular Ca store. 2105 41


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