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Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The synthesis of dibutylchloromethyltin chloride, a new covalent inhibitor of the mitochondrial ATP synthase [oligomycin-sensitive ATPase (adenosine triphosphatase)] complex is described, together with a method for preparing dibutylchloro[(3)H]methyltin chloride. 2. Studies with the yeast mitochondrial oligomycin-sensitive ATPase complex show that dibutylchloromethyltin chloride inhibits both the membrane-bound enzyme and also the purified Triton X-100-dispersed preparation. 3. F(1)-ATPase is not inhibited even at 500nmol of dibutylchloromethyltin chloride/mg of protein, and the general inhibitory properties are similar to those of triethyltin, oligomycin and dicyclohexylcarbodi-imide, known energy-transfer inhibitors of oxidative phosphorylation. 4. Binding studies with yeast submitochondrial particles show that dibutylchloromethyltin chloride antagonizes the binding of triethyl[(113)Sn]tin, indicating that there is an interaction between the two inhibitor-binding sites. 5. Unlike triethyltin, inhibition by dibutylchloromethyltin chloride is due to a covalent interaction which titrates a component of the inner mitochondrial membrane present at a concentration of 8-9nmol/mg of protein. 6. All of the labelled component can be extracted with chloroform/methanol (2:1, v/v), and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of the chloroform/methanol extract indicates that the labelled component has an apparent mol.wt. of 6000-8000. However, t.l.c. reveals the presence of only one labelled component which is lipophilic and non-protein and is distinct from the free inhibitor, mitochondrial phospholipids and the dicyclohexylcarbodi-imide-binding protein (subunit 9). 7. Inhibition of mitochondrial ATPase and oxidative phosphorylation is correlated with specific interaction with a non-protein lipophilic component of the mitochondrial inner membrane which is proposed to be a co-factor or intermediate of oxidative phosphorylation.
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PMID:Dibutylchloromethyltin chloride, a covalent inhibitor of the adenosine triphosphate synthase complex. 14 60

Venturicidin is a specific inhibitor of aerobic growth of yeast and has no effect on fermentative growth, a result which is consistent with its known mode of action on mitochondrial oxidative phosphorylation. Venturicidin-resistant mutants of Saccharomyces cerevisiae have been isolated and form two general classes: class 1, nuclear mutants which are resistant to a variety of mitochondrial inhibitors and uncouplers, and class 2, mitochondrial mutants of phenotype VENR OLYR and VENR TETR in vivo. VENR OLYR mutants show a high degree of resistance to venturicidin and oligomycin at the whole cell and mitochondrial ATPase level but, in contrast, no resistance at the mitochondrial level is observed with VENR TETR mutants. Venturicidin resistance/sensitivity can be correlated with two binding sites on mitochondrial ATPase, one of which is common to the oligomycin binding site and the other is common to the triethyl tin binding site. Biochemical genetic studies indicate that two mitochondrial genes specify venturicidin resistance/sensitivity and that the mitochondrial gene products are components of the mitochondrial ATPase complex.
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PMID:Studies on energy-linked reactions: isolation and properties of mitochondrial venturicidin-resistant mutants of Saccharomyces cerevisiae. 23 35

Inhibition of ATPase activities by triethyltin (TET), diethyltin (DET), monoethyltin (MET), and trimethyltin (TMT) was studied in homogenates of brain and liver from adult and neonatal rats. In the adult, sensitivities were as follows: mitochondrial ATPase of liver much greater than Na+, K+-ATPase of brain approximately equal to mitochondrial ATPase of brain greater than nonspecific ATPase of brain and liver. MET did not produce significant inhibition. ATPase activities in brain and liver homogenates from TET-treated adult rats did not differ from controls. Mitochondrial ATPase in brain homogenates from 5-day-old rats was two orders of magnitude more sensitive to TET than brain homogenates from adult rats (IC50 of 2.5 microM in the 5-day-old neonate vs 260 microM in the adult). By contrast, isolated mitochondria and synaptosomal fractions from adult and neonatal brains were equally sensitive to TET (IC50 = 1-3 microM). At 10 days of age, following the onset of myelination, the IC50 for TET inhibition of brain mitochondrial ATPase increased to 71 microM. Myelin added directly to isolated mitochondria also reduced TET-induced inhibition. It is concluded that in vivo brain tin concentrations in 5-day-old rats following a neurotoxic dose of TET are sufficient to inhibit brain mitochondrial ATPase, whereas in adults, tin concentrations are insufficient for inhibition. In the adult rat, TET binding to myelin appears to prevent inhibition of brain mitochondrial ATPase, and the target of toxic action may be myelin. In the neonateal rat, TET may inhibit oxidative phosphorylation in unmyelinated brain tissue, leading to neuronal cell death.
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PMID:Alkyltin inhibition of ATPase activities in tissue homogenates and subcellular fractions from adult and neonatal rats. 296 35

The limiting membranes of pituitary growth hormone and prolactin secretory granules contain a Mg2+-ATPase sensitive to anions. This enzyme is in many ways similar to mitochondrial ATPase. The enzyme was potently inhibited by oligomycin (Ki 6.5 X 10(-9) M), and was much more sensitive to the inhibitor than pituitary mitochondrial ATPase (Ki 2.7 X 10(-7) M). In contrast, the enzyme activity of intact secretory granules was only sparingly inhibited by oligomycin (maximal inhibition close to 30% at 5 X 10(-4) M). However, oligomycin (5 microM) did diminish to basal levels the enhanced granule ATPase activity observed in the presence of a stimulatory anion (25 mM sodium sulfite). Other compounds known to inhibit the proton translocating mitochondrial ATPase were also tested for their ability to inhibit the secretory granule ATPase. A similar pattern of limited inhibition in granules and greater sensitivity in isolated membranes was seen with the inhibitors N,N-dicyclohexylcarbodiimide and efrapeptin. In contrast, tri-n-butyltin chloride was a potent inhibitor of the ATPase of intact granules, and the susceptibility of the enzyme to inhibition by this compound was less after isolation of membranes. These observations suggest that pituitary secretory granule membrane ATPase may have a proton pumping function similar to that of the mitochondrial enzyme. In addition, the data imply that the inhibitor binding site(s) may be masked, inaccessible, or ineffective in intact granules, but exposed (or activated) in isolated membranes. The greater sensitivity of granule ATPase to tri-n-butyltin chloride, in contrast to the greater sensitivity of membrane ATPase to the other inhibitors, indicates that the tin compound may be effective at a membrane site(s) distinct from the others, or that the mechanism of inhibition is different.
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PMID:Inhibitor studies with adenohypophyseal granule membrane ATPase. Evidence for a membrane environment which modulates sensitivity to inhibitors. 614 4

Synaptic vesicles prepared from bovine corpus striatum exhibit an ATPase activity that is insensitive to ouabain and specific inhibitors of mitochondrial ATPase, but that is stimulated by proton ionophores and inhibited by sulfhydryl reagents. Low concentrations of orthovanadate, DCCD and tributyl tin are also ineffective as inhibitors of the vesicle-associated activity. The properties of the synaptic vesicle enzyme suggest that this ATPase may be similar to that of clathrin-coated vesicles, and to one of the activities described in preparations of adrenal chromaffin granule membranes.
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PMID:Properties of the bovine striatal synaptic vesicles ATPase. 623 19

Bovine submitochondrial particles prepared in the presence of GTP (G-SMP), as well as G-SMP washed in 150 mM KCl, catalyzed unisite ATP hydrolysis with a first order rate constant of 0.12 s-1. This rate constant remained unchanged at ATP concentrations < 0.06 microM but increased sharply at higher ATP concentrations, presumably because of ATP binding to other catalytic or regulatory sites. Pretreatment of the particles with oligomycin greatly inhibited unisite ATP binding, in agreement with previous findings. Pretreatment of the particles with N,N'-dicyclohexylcarbodiimide had a slight effect on unisite ATP binding, whereas pretreatment with the inhibitors venturicidin and tributyl(or triphenyl)tin chloride had no effect. Titration of unisite ATPase activity with increasing concentrations of oligomycin or efrapeptin resulted in sigmoidal inhibition curves, as though more than a single inhibition site was being titrated by each inhibitor. Venturicidin and organotin compounds had little effect on the ATPase activity of SMP at [ATP] < or = [F1] and did not cause 100% inhibition at [ATP] >> [F1]. By analogy to our previous studies on the inhibition of the ubiquinol-cytochrome c reductase complex by antimycin (Hatefi, Y., and Yagi, T. (1982) Biochemistry 24, 6614-6618), it is proposed that venturicidin and organotin compounds freeze the structure of the F0 sector of the ATP synthase complex in such a manner that prevents the subunit molecular motions required for rapid proton flux but allows a slow proton flux generated by ATPase activity at low ATP concentrations.
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PMID:Studies on the mechanism of oxidative phosphorylation. Different effects of F0 inhibitors on unisite and multisite ATP hydrolysis by bovine submitochondrial particles. 838 May 71