Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mycotoxin, cyclopiazonic acid (CPA), inhibits the Ca2+-stimulated ATPase (EC 3.6.1.38) and Ca2+ transport activity of sarcoplasmic reticulum (Goeger, D. E., Riley, R. T., Dorner, J. W., and Cole, R. J. (1988) Biochem. Pharmacol. 37, 978-981). We found that at low ATP concentrations (0.5-2 microM) the inhibition of ATPase activity was essentially complete at a CPA concentration of 6-8 nmol/mg protein, indicating stoichiometric reaction of CPA with the Ca2+-ATPase. Cyclopiazonic acid caused similar inhibition of the Ca2+-stimulated ATP hydrolysis in intact sarcoplasmic reticulum and in a purified preparation of Ca2+-ATPase. Cyclopiazonic acid also inhibited the Ca2+-dependent acetylphosphate, p-nitrophenylphosphate and carbamylphosphate hydrolysis by sarcoplasmic reticulum. ATP protected the enzyme in a competitive manner against inhibition by CPA, while a 10(5)-fold change in free Ca2+ concentration had only moderate effect on the extent of inhibition. CPA did not influence the crystallization of Ca2+-ATPase by vanadate or the reaction of fluorescein-5'-isothiocyanate with the Ca2+-ATPase, but it completely blocked at concentrations as low as 1-2 mol of CPA/mol of ATPase the fluorescence changes induced by Ca2+ and [ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA) in FITC-labeled sarcoplasmic reticulum and inhibited the cleavage of Ca2+-ATPase by trypsin at the T2 cleavage site in the presence of EGTA. These observations suggest that CPA interferes with the ATP-induced conformational changes related to Ca2+ transport. The effect of CPA on the sarcoplasmic reticulum Ca2+-ATPase appears to be fairly specific, since the kidney and brain Na+,K+-ATPase (EC 3.6.1.37), the gastric H+,K+-ATPase (EC 3.6.1.36), the mitochondrial F1-ATPase (EC 3.6.1.34), the Ca2+-ATPase of erythrocytes, and the Mg2+-activated ATPase of T-tubules and surface membranes of rat skeletal muscle were not inhibited by CPA, even at concentrations as high as 1000 nmol/mg protein.
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PMID:Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum. 253 Feb 15

A mutant of ATP synthase subunit c was isolated in which the essential aspartate was exchanged from position 61 on transmembrane helix-2 to position 24 on transmembrane helix-1 (Miller, M. J., Oldenburg, M., and Fillingame, R. H. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 4900-4904). The H+ transporting ATP synthase function of the Ala24-->Asp/Asp61-->Gly mutant is not optimal, and cells grow more slowly than wild type. Twenty-three third-site suppressor mutants with optimized function were isolated in this study. Ten of the optimizing mutations were located to helix-2 of subunit c, and seven of these fell in residues Phe53, Met57, and Met65. The side chains of these three residues are proposed to form a hydrophobic surface on transmembrane helix-2, which participates in the presentation or occlusion of the essential aspartate carboxyl group during proton translocation. The other 13 optimizing mutations were located to subunit a, and 10 of these fell in residues Ala217, Ile221, and Leu224. These three residues are proposed to lie on one face of a transmembrane alpha-helix that includes the essential Arg210 residue. This helix is proposed to interact with the transmembrane bihelical unit of subunit c during protonation and deprotonation of the essential Asp24 in the mutant or Asp61 in wild type.
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PMID:Transmembrane helix-helix interactions in F0 suggested by suppressor mutations to Ala24-->Asp/Asp61-->Gly mutant of ATP synthase subunit. 830 May 84

An acidic microenvironment formed by vacuolar ATPase (V-ATPase) expressed in plasma membranes of osteoclasts is thought to be indispensable for bone resorption. This study examined the efficacy of a novel V-ATPase inhibitor, FR202126, in reducing alveolar bone loss caused by experimental periodontitis in rats. FR202126 inhibited H+ transport in plasma membrane vesicles of murine osteoclasts, whereas FR202126 exerted no effect on H+ transport of mitochondrial ATPase or gastric H+,K+-ATPase, indicating that FR202126 is a specific inhibitor of V-ATPase. As expected from the mechanism, FR202126 remarkably inhibited in vitro bone resorption whatever bone resorptive factors were added. Moreover, FR202126 was also able to exert an inhibitory effect on in vivo bone resorption. Experimental periodontitis was induced by ligature wire tied around the contact between the first and second maxillary molars. Insertion of ligature wire for 7 days induced alveolar bone destruction by activating osteoclasts. Oral administration of FR202126 (u.i.d.) significantly prevented alveolar bone loss in experimental periodontitis which may offer a new approach to treatment of periodontal disease.
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PMID:A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats. 1640 38

Bombyx mori (B. mori), silkworm, is one of the most important economic insects in the world, while phoxim, an organophosphorus (OP) pesticide, impact its economic benefits seriously. Phoxim exposure can damage the brain, fatbody, midgut and haemolymph of B. mori. However the metabolism of proteins and carbohydrates in phoxim-exposed B. mori can be improved by Titanium dioxide nanoparticles (TiO2 NPs). In this study, we explored whether TiO2 NPs treatment can reduce the phoxim-induced brain damage of the 5th larval instar of B. mori. We observed that TiO2 NPs pretreatments significantly reduced the mortality of phoxim-exposed larva and relieved severe brain damage and oxidative stress under phoxim exposure in the brain. The treatments also relieved the phoxim-induced increases in the contents of acetylcholine (Ach), glutamate (Glu) and nitric oxide (NO) and the phoxim-induced decreases in the contents of norepinephrine (NE), Dopamine (DA), and 5-hydroxytryptamine (5-HT), and reduced the inhibition of acetylcholinesterase (AChE), Na+/K+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase activities and the activation of total nitric oxide synthase (TNOS) in the brain. Furthermore, digital gene expression profile (DGE) analysis and real time quantitative PCR (qRT-PCR) assay revealed that TiO2 NPs pretreatment inhibited the up-regulated expression of ace1, cytochrome c, caspase-9, caspase-3, Bm109 and down-regulated expression of BmIap caused by phoxim; these genes are involved in nerve conduction, oxidative stress and apoptosis. TiO2 NPs pretreatment also inhibited the down-regulated expression of H+ transporting ATP synthase and vacuolar ATP synthase under phoxim exposure, which are involved in ion transport and energy metabolism. These results indicate that TiO2 NPs pretreatment reduced the phoxim-induced nerve toxicity in the brain of B. mori.
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PMID:Molecular mechanisms of reduced nerve toxicity by titanium dioxide nanoparticles in the phoxim-exposed brain of Bombyx mori. 2497 66