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

ATPase inhibitor protein, which blocks mitochondrial ATPase activity by forming an enzyme-inhibitor complex, was found to be synthesized as a larger precursor in a cell-free translation system directed by yeast mRNA. Other protein factors, which stabilize latent ATPase by binding to the enzyme-inhibitor complex, were also found to be formed as larger precursors. The precursor of ATPase inhibitor protein was transported into isolated yeast mitochondria and was cleaved to the mature peptide in the mitochondria. Impaired mitochondria lacking phosphorylation activity could not convert the precursor to the mature form. Neither antimycin A nor oligomycin alone exhibited a marked effect on the transport-processing of the precursor by intact mitochondria. However, when antimycin A was added with oligomycin, the transport-processing was markedly inhibited. The processing was also strongly inhibited by an uncoupler, carbonylcyanide p-trifluoro-methoxyphenyl hydrazone. The inhibition by the uncoupler was not relieved by ATP added externally. It is concluded that the transport-processing of precursor proteins requires intact mitochondria with a potential difference across the inner membrane.
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PMID:Cell-free synthesis of mitochondrial ATPase inhibitor precursor and its transport into yeast mitochondria. 635 96

Mitochondrial adenosine triphosphatase (ATPase) of the ciliate protozoon Tetrahymena pyriformis ST is completely inhibited by antiserum prepared against F1-ATPase purified from Schizosaccharomyces pombe, and by naturally occurring inhibitor proteins from this yeast and from bovine heart mitochondria. An ATPase inhibitor protein is also present in extracts of T. pyriformis. Mitochondrial ATPase of T. pyriformis is only partially inhibited by the F0-ATPase inhibitors N,N'-dicyclohexylcarbodiimide, oligomycin, leucinostatin, triethyltin sulphate and venturicidin, and (at high titres) by the F1-ATPase inhibitors Dio-9, efrapeptin, 4-chloro-7-nitrobenzofurazan and spegazzinine. Aurovertin, citreoviridin and quercetin were not inhibitory. Resistance to inhibitors distinguishes this mitochondrial ATPase from all those previously examined.
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PMID:Effects of inhibitors on mitochondrial adenosine triphosphatase of Tetrahymena pyriformis ST. 646 27

The methyl 4-azidobenzimidate derivative of the naturally occurring ATPase inhibitor protein (IF1) of mitochondria binds to the beta subunits of soluble F1-ATPase upon photoactivation [Klein, G., Satre, M., Dianoux, A.-C., & Vignais, P. V. (1981) Biochemistry 20, 1339--1344]. A number of specific ATPase inhibitors, namely, 4-chloro-7-nitrobenzofurazan (NBF-Cl), efrapeptin, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSBA), phenylglyoxal, aurovertin, tridentate ferrous bathophenanthroline, and octylguanidine (referred to hereafter as "artificial" inhibitors), are also considered to bind to the beta subunit, and there is strong evidence that the first three bind at the active site. Since the inhibition by IF1 of complex V ATPase activity can be reversed by incubation of the inhibited complex at pH 8.0, this system was used to investigate whether the inhibitions brought about by IF1 and the artificial inhibitors were independent, mutually interfering, or mutually exclusive. The experiments were carried out in two ways. (a) Complex V was first maximally inhibited by IF1. Then an artificial inhibitor was added and allowed to react. Excess artificial inhibitor was removed by precipitation of the doubly inhibited complex V with ammonium sulfate and resuspension in inhibitor-free buffer at pH 8.0. Incubation at pH 8.0 released the inhibition due to IF1. However, it was found that the factor that controlled reemergence of ATPase activity was the degree of inhibition exerted by the artificial inhibitor. When the artificial inhibitor was removed first (which was done by addition of dithiothreitol when the artificial inhibitor was NBF-Cl), then reemergence of activity depended on incubation at pH 8.0 to reverse the inhibition due to IF1. These results indicated that IF1-inhibited complex V could be independently inhibited by various artificial inhibitors. The artificial inhibitors used in this type of study were NBF-Cl, efrapeptin, aurovertin, FSBA, and phenylglyoxal. (b) Complex V was first treated with the artificial inhibitor (ferrous bathophenanthroline or octylguanidine) and then with IF1. Results showed that prior treatment of complex V with these inhibitors did not interfere with IF1 subsequently exerting maximal and reversible inhibition. The above results have been discussed in view of the recent finding that F1-ATPase contains two functional and interacting hydrolytic sites [Grubmeyer, C., & Penefsky, H.S. (1981) J. Biol. Chem. 256, 3718--3727].
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PMID:Independent inhibitions of mitochondrial complex V by the adenosinetriphosphatase inhibitor protein and active-site modifiers. 646 71

Messenger RNA coding mitochondrial ATPase inhibitor protein, a small peptide comprised of 63 amino acid residues, was separated from a large quantity of mRNAs of larger molecules by high speed gel permeation chromatography. Messenger RNA coding a small stabilizing factor of inactivated F1F0-ATPase complex, which is also comprised of 63 amino acids, was recovered in the same fraction as the ATPase inhibitor, whereas mRNA for a large stabilizing factor with an apparent molecular weight of 15,000 was recovered in a fraction of slightly larger molecules. ATPase inhibitor precursor labeled with various kinds of radioactive amino acids was prepared separately by cell-free translation with the purified mRNA, and the amino terminal sequence of the precursor was examined. It was demonstrated that an extra peptide of 21 amino acid residues, including 5 leucine, 4 serine, 1 glycine, and 1 methionine residues, is located at the amino terminus of the ATPase inhibitor precursor.
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PMID:Partial amino terminal sequence of the precursor of mitochondrial ATPase inhibitor protein synthesized with mRNA partially purified by gel permeation chromatography. 661 14

Peptide analogs which correspond to the conserved region of the natural ATPase inhibitor protein from beef heart, Candida utilis, and Saccharomyces cerevisiae mitochondria were synthesized by solid-phase methodologies and tested for ATPase inhibitory activity. These peptides were found to be potent inhibitors of F1-ATPase-catalyzed ATP hydrolysis in acidic reaction media, having I50 values of 1.1 +/- 0.4 microM, 10 +/- 5 microM, and 48 +/- 19 microM, respectively. These results closely match those obtained for the naturally occurring inhibitor proteins. Additional peptides that correspond to the beef heart beta-subunit near the binding site of the beef heart inhibitor protein and that possess a substantial homology with the conserved region of the inhibitor protein were synthesized. Several of these peptides were found to be inhibitors of the ATPase activity. The best inhibitor, with an I50 value of 20 +/- 3 microM, was the peptide resembling the beef heart beta-subunit comprising amino acids 394-413. This peptide most closely resembles the peptides derived from the conserved region of the inhibitor protein. The insertion of five glycine residues between the charge clusters in the beta-394-413 peptide resulted in a peptide which was able to stimulate the hydrolysis of ATP.
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PMID:Peptide analogs of the beef heart mitochondrial F1-ATPase inhibitor protein. 833 48

In the present study we compared the quantitatively most important, Pi-activated mechanisms for conserving ATP during ischemia in dog and rat cardiac muscle. Earlier studies by ourselves showed that dog heart, like all slow heart rate mammalian hearts examined, possesses the ability to inhibit its mitochondrial ATPase by binding IF1, the ATPase inhibitor protein, during ischemia. Rat heart, like other fast heart rate mammalian hearts studied, does not. The present study demonstrated that this IF1-mediated ATPase inhibition in ischemic dog heart, as in other slow heart rate hearts, appears to depend on matrix space acidification mediated largely by Pi-H+ symport via the mitochondrial Pi carrier. The present study further confirmed that maximal glycolytic flux rates are five- to sixfold greater in ischemic rat than in ischemic dog heart. Both of these systems are activated by increasing Pi concentration ([Pi]) during ischemia, and both appear to be regulated somewhat differently in dog than in rat heart. Thus intact dog heart mitochondria exhibited a [Pi]-dependent ATPase inhibition at low external pH, whereas rat heart mitochondria did not. The [Pi] required for maximal ATPase inhibition in dog heart mitochondria was approximately 6 mM. Although both dog and rat heart phosphofructokinase were stimulated by Pi, the enzyme in dog heart was maximally activated by approximately 6 mM Pi, whereas the rat heart enzyme required only approximately 3 mM Pi for its maximal stimulation under otherwise identical conditions. The most active nonmitochondrial ATPase in ischemic dog and rat cardiac muscle, the Ca(2+)-activated actomyosin ATPase, accounted for approximately one-half of the total nonmitochondrial ATPase activity in each species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of ATP conservation during ischemia in slow and fast heart rate hearts. 843 Jul 69

The ATPase inhibitor protein of the rat liver mitochondrial ATP synthase/ATPase complex has been cloned from a rat liver cDNA library, and its nucleotide sequence determined. The sequence is highly homologous to both the bovine heart (approximately 70%) and the yeast inhibitor proteins (approximately 40%). The deduced protein sequence is 107 amino acids in length, and based on homology to the bovine heart protein, the first 25 N-terminal amino acids encode a putative mitochondrial targeting sequence. The "mature" protein (without the targeting sequence) fused to the maltose binding protein has been overexpressed in Escherichia coli. The maltose binding protein was used as a handle for the development of a rapid one-step purification of the fusion protein by affinity chromatography on an amylose resin. The purified fusion protein was cleaved with Factor Xa protease at the fusion junction, and the resulting ATPase inhibitor protein was purified to > 90% purity. The purified, overexpressed inhibitor protein displays normal inhibitor activity. The protein inhibits ATP hydrolysis catalyzed by the ATP synthase/ATPase complex in submitochondrial particles in a manner kinetically indistinguishable from the same protein purified from rat liver mitochondria, and exhibits a specific activity of approximately 10,000 units/mg. The secondary structure of the inhibitor protein was determined by circular dichroism spectropolarimetry. The experimentally determined structure shows a high content of alpha-helix and is in good agreement with sequence-based structural predictions. As the function of the inhibitor protein is known to exhibit a high dependence on pH, a study of the pH dependence of inhibitor secondary structure was performed. It is shown that as pH is lowered, conditions which activate inhibitory capacity, the protein loses significant alpha-helical structure. This is the first report of the overexpression in E. coli of a functional ATPase inhibitor protein. Secondary structural analysis of this protein indicates that conversion from its active to its inactive form involves a significant conformational change.
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PMID:Regulation of the mitochondrial ATP synthase/ATPase complex: cDNA cloning, sequence, overexpression, and secondary structural characterization of a functional protein inhibitor. 844 67

Four cDNAs for the import precursors of oligomycin sensitivity conferring protein (OSCP), ATPase inhibitor protein (IF1) and subunit cs (encoded by P1 and P2 genes) of rat mitochondrial H(+)-ATP synthase have been cloned from a rat cDNA library. The import precursors and the mature polypeptides of rat OSCP, IF1, subunit c (P1) and subunit c (P2) consisted of 23/190, 25/82, 61/75 and 66/75 amino acids, respectively.
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PMID:Molecular cloning and sequence of cDNAs for the import precursors of oligomycin sensitivity conferring protein, ATPase inhibitor protein, and subunit c of H(+)-ATP synthase in rat mitochondria. 844 8

The well characterized subunits of the bovine ATP synthase complex are the alpha, beta, gamma, delta, and epsilon subunits of the catalytic sector, F1; the ATPase inhibitor protein; and subunits a, b, c, and d, OSCP (oligomycin sensitivity-conferring protein), F6, and A6L, which are present in the membrane sector, F0, and the 45-A-long stalk that connects F1 to F0. It has been shown recently that bovine ATP synthase preparations also contain three small polypeptides, designated e, f, and g, with respective molecular masses of 8.2, 10. 2, and 11.3 kDa. To ascertain their involvement as bona fide subunits of the ATP synthase and to investigate their membrane topography and proximity to the above ATP synthase subunits, polyclonal antipeptide antibodies were raised in the rabbit to the COOH-terminal amino acid residues 57-70 of e, 75-86 of f, and 91-102 of g. It was shown that (i) e, f, and g could be immunoprecipitated with anti-OSCP IgG from a fraction of bovine submitochondrial particles enriched in oligomycin-sensitive ATPase; (ii) the NH2 termini of f and g are exposed on the matrix side of the mitochondrial inner membrane and can be curtailed by proteolysis; (iii) the COOH termini of all three polypeptides are exposed on the cytosolic side of the inner membrane; and (iv) f cross-links to A6L and to g, and e cross-links to g and appears to form an e-e dimer. Thus, the bovine ATP synthase complex appears to have 16 unlike subunits, twice as many as its counterpart in Escherichia coli.
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PMID:Membrane topography and near-neighbor relationships of the mitochondrial ATP synthase subunits e, f, and g. 870 68

The isolation and properties of F1-mitochondrial ATPase from rat testis are described. The isolation medium involves a chloroform extraction, and it is suitable even with small amounts of starting material that have a relatively low specific activity as in the case of rat testis submitochondrial particles. The isolated enzyme from rat testis had a specific activity of 30-45 mumol Pi/min/mg protein, which could be increased up to 90 mumol Pi/min/mg protein only in the presence of bicarbonate and maleate. The isolated enzyme represented less than 0.6% of the initial membrane proteins. It exhibited a typical five-band pattern in sodium dodecyl sulfate gel electrophoresis. However, it showed a ratio of subunits alpha:beta higher than the heart enzyme; its significance is unknown. The purified enzyme was cold labile and inhibited by natural ATPase inhibitor protein from bovine heart mitochondria and by dicyclohexylcarbodiimide. The results presented suggest that the low ATPase activity of testis submitochondrial particles is due to a reduced content of the F1-ATPase.
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PMID:Isolation and comparative studies of mitochondrial F1-ATPase from rat testis and beef heart. 911 89


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