ATP: The Fuel for Life
Often referred as “molecular currency” for intracellular energy transfer, Adenosine Triphosphate (ATP) functions as a chemical fuel by powering many organic processes of life. ATP generation is the principle energy generating procedure found in all forms of life. ATP is the fuel for the operation of almost all metabolic pathways of the cell. In an ATP molecule, two high-energy phosphate bonds, called phosphoanhydride bonds, are responsible for high energy content. Hydrolysis of the third phosphate group produces adenosine diphosphate (ADP) and inorganic phosphate (Pi), along with considerable release of energy. ADP can absorb energy and regain the group to regenerate an ATP molecule to maintain constant ATP concentration.
Other than supporting almost all the cellular functions that require energy, ATP also works as a coenzyme during phosphorylation reactions. Besides, ATP has crucial role in RNA and DNA synthesis and in amino acid activation during protein synthesis. Khakh and Burnstock, established that ATP also serves as a critical signaling molecule that allows inter and intracellular communications. The ubiquitous distribution of ATP allows for signaling functions that have a uniquely broad influence on physiological functioning .
Estimates show that the normal body uses 40 kg of ATP on a daily basis; hence ATP production is one of the most frequent processes occurring in the body . The aggregate amount of ATP in the human body is about 0.1 Mole. The energy utilized every day by an adult requires the hydrolysis of 100 to 150 Moles of ATP. This implies every ATP molecule must be reused 1000 or more multiple times in a day . ATP cannot be stored and so its synthesis is closely linked to its consumption. ATP is produced under aerobic conditions through glycolysis, citric acid cycle/oxidative phosphorylation and beta-oxidation and under anaerobic condition through fermentation, photophosphorylation and replenishment reactions catalyzed by nucleoside diphosphate kinase .
ATP is synthesized from its precursor, ADP, by ATP synthases. These enzymes are found in the cristae and the inner membrane of mitochondria, the thylakoid membrane of chloroplasts, and the plasma membrane of bacteria . Usually, there is a general understanding that ATP generation occurs in mitochondria. However, in the case of bacteria and archaea that lack mitochondria, ATP synthase is found in their plasma membrane. Additionally, ATP synthases are licensed to inhabit the chloroplast of plant cells. The structure and procedure of ATP synthesis is similar in all three locations except that light energy excites electrons enabling transmembrane movement of H+ ions in chloroplasts. The general nomenclature of ATP synthase as FoF1 changes to CFoCF1 for chloroplast ATP synthase and ECFoECF1 for Escherichia coli’s ATP synthase .
ATP synthesis is the most widespread chemical reaction inside the biological world. ATP synthase is the very last enzyme in oxidative phosphorylation pathway that makes use of electrochemical energy to power ATP synthesis [7, 8, 9, 10]. ATP synthase is one of the most ubiquitous and plentiful protein on the earth, accountable for the reversible catalysis of ATP to ADP and Pi. This is also one of the most conserved proteins in Bacteria, Plants and Mammals with more than 60% of the amino-acid residues of the catalytic β-subunit resisting evolution . ATP synthases are classified as F (Phosphorylation Factor), V (Vacuole), A (Archaea), P (Proton) or E (Extracellular) ATPases based on their functional differences, although they all catalyze ATP synthesis and/or hydrolysis.
The mitochondrial ATP synthase is a multi-subunit protein complex having an approximate molecular weight of 550 kDa. The human mitochondrial ATP synthase or F1/F0 ATPase or complex V (EC 184.108.40.206) is the fifth component of oxidative phosphorylation chain . This enzyme is the smallest known biological nanomotor and plays a crucial role in ATP generation. In plants, energy acquired from photons is transferred through photosynthetic electron transport chain (ETC), which induces an electrochemical gradient to build up across the membrane. ATP synthase uses energy conferred by this electrochemical gradient for phosphorylation of ADP to generate ATP .
Electrochemical gradient and the Chemiosmotic Theory
The chemiosmotic hypothesis proposed by Peter Mitchell states: “The differential of electrochemical activity of the hydrogen and hydroxyl ions across the membrane generated by electron transport causes the specific translocation of hydroxyl and hydrogen ions from the active centre of the so called ATPase system thus effectively dehydrating ADP+P”. This pioneered the research on the coupling of the ETC and ATP synthesis. Basically, protons are pumped across the inner mitochondrial membrane as electrons pass through the electron transfer chain. This induces a proton gradient, with a decreased pH in the intermembrane space and an increased pH in the matrix of the mitochondria. The proton gradient and membrane potential are the major forces involved in ATP synthesis. Essentially, the pH gradient acts as a ‘battery’ which stores the electrochemical energy to be used later for ATP production.
It is well established that the electrochemical potential of protons delivered by electron transfer chains across the mitochondrial, chloroplast or bacterial membrane provides the energy for ATP synthesis . Cellular respiration in the mitochondria is a widely studied process that incorporates chemiosmosis for the production of ATP.
Mitochondria, the chief organelles producing ATP, are absent in prokaryotic organisms. In the absence of mitochondria, archaea and bacteria maneuver chemiosmosis to produce ATP through photophosphorylation. This process, taking place across the inner membrane, is coherent with the ETC, proton gradient, and chemiosmosis of H+ .
Electrons from NADH, FADH and other oxidizable substrates pass through the complexes of the ETC arranged asymmetrically in the inner membrane of mitochondria. Electron flow is accompanied by the transfer of protons (H+) across the membrane, producing both chemical gradient (ΔpH) and electric gradient (ΔΨ). The electrochemical energy built through the difference in proton concentration and separation of charge across inner mitochondrial membrane translates to the proton motive force (PMF). The PMF drives the synthesis of ATP as proton flow back into the matrix through the proton specific channels (F0) component of the ATP synthase. This also satisfies a main criterion stated by Mitchell for the chemiosmotic coupling to occur: the inner mitochondrial membrane must be impermeable to protons. Thus, protons are compelled to re-enter matrix through F0 while F1 catalyzes the synthesis of ATP .
Feniouk, described ATP synthesis/hydrolysis by the reaction:
ATP synthase is powered by the transmembrane electrochemical proton potential difference measured in Joules per mole (J mol-1) and is defined as:
where, P and N denote the positively and the negatively charged sides of the coupling membrane; F is Faraday constant (96 485 C mol-1); R is the molar gas constant (8.314 J mol-1K-1), T is the temperature in Kelvin, and ΔΨ is the transmembrane electrical potential difference in volts. Protons, being charged particles, are driven by from the positively charged side to the negatively charged side. The value of gives energy required or released when 1 Mole of proton move across the membrane. During hydrolysis, the enzyme operates as ATP-driven proton pump generating The equation for reaction catalyzed is:
is more conveniently replaced by proton-motive force (pmf) measured in millivolts and defined as:
At room temperature (25oC),
The pmf value, for most biological membranes involved in ATP synthesis, lies between 120 and 200 mV between 11.6 and 19. 3 kJ mol-1). This energy is capitalized by ATP synthase to catalyze the formation of ATP from ADP and inorganic Phosphate .
Structural Assembly of F1F0 ATP Synthase
E.coli ATPase/synthase comprises of 8 different subunits. There are only slight variations in its structure in the chloroplast and in the mitochondria. The chloroplast ATPase has two isoforms and in the mitochondria it has 7-9 additional subunits. Besides these differences, ATPases are structurally and functionally similar. The ATP synthase, also called Complex V, has two major subunits designated F0 and F1. The F0 part, bound to inner mitochondrial membrane is involved in proton translocation, whereas the F1 part found in the mitochondrial matrix is the water soluble catalytic domain. F1 is the first factor recognized and isolated from bovine heart mitochondria and is involved in oxidative phosphorylation. It was named so from the term ‘Fraction 1’. F0 was named so as it is a factor that conferred oligomycin sensitivity to soluble F1 .
The structure of enzyme ATP synthase mimics an assembly of two motors with a shared common rotor shaft and stabilized by a peripheral stator stalk. The F1 part of ATP synthase is made up of 8 subunits, 3α, 3β, γ, δ and ε, where the γ, δ and ε subunits add up to the central stalk (or the rotor shaft) and an alternate arrangement of 3α and 3β form a hexameric ring with a central cavity. The γ subunit inserted in the central cavity protrudes out to meet ε which binds on its side and together they bind the F0. Bacterial F0 has the simplest subunit structure consisting a1, b2 and c10-14 subunits. Eukaryotic F0 has several subunits including d, F6 and the oligomycin sensitivity-conferring protein (OSCP). Subunits b, d, F6 and OSCP form the peripheral stalk, which connect both F1 and F0 and keep the stators (F1-αβ3 and F0a) from spinning along with the rotor (γδε and F0c). Other additional subunits such as subunit e, f, g, and A6L extending over the membrane cohort with F0 [5, 10, 20].
Rotational catalysis and ATP generation
Paul Boyer proposed a simple catalytic scheme, commonly known as the binding change mechanism, which predicted that F-ATPase implements a rotational mechanism in the catalysis of ATP . The movement of subunits within the ATP synthase complex plays essential roles in both transport and catalytic mechanisms. Each catalytic site would achieve and change three conformations during a complete 360° turnover and a cycle would be completed at a different catalytic site with a rotation of 120°. When a nucleotide binds to ATPase, it undergoes a conformational change in order to be tightly bound to ATP. Another subsequent change in conformation brings about the release of ATP. These conformational changes are accomplished by rotating the inner core of the enzyme. The core itself is powered by the proton motive force conferred by protons crossing the mitochondrial membrane.
Masamitsu et. al reviewed that 3αs and 3βs are positioned alternatingly in a circle, each having different function as well as conformation . Although the α subunit has bound ATP, it neither releases the ATP nor participates in the reaction. Each β subunit has three catalytic sites that differ in nucleotide binding states . The first is occupied by Mg·AMP-PNP1 (an analog of ATP), the second is occupied by Mg·ADP, and the third is empty (no bound nucleotide); these sites are termed βT, βD, and βE, respectively. The F1 system has inherent asymmetry within the β subunit conformations, which depend on orientation of the γ subunit. When the γ subunit rotates, it induces conformational changes in each β subunit conducive to the surface of γ subunit in contact. The rotation of the shaft (γ subunit) is effectuated by the flow of protons into the matrix through F0, which connectedly provides the energy for the release of ATP .
Conformational transitions that are significant in rotational catalysis are directed by the passage of protons through the F0 assembly of ATP synthase. The flow of protons through the F0 pore brings about the rotation of the cylinder of c subunits and the attached γ subunit around the axis of γ. The γ subunit runs along the central canal of the (αβ)3 assembly, which is held stationary relative to the membrane surface by the b2 and δ subunits and meets the c ring via δ and ε subunits. With every rotation of 120°, γ comes into contact with a different β subunit, and the contact forces that β subunit into the βE conformation. The three subunits switch conformations in such a way that when one holds the βE conformation, one of its flanking subunit assumes the βD form, and the other takes βT form. As a consequence of a complete rotation of the γ subunit, each β subunit courses through all three possible conformations and three ATP’s are synthesized and delivered by the enzyme.
A sturdy prediction of the binding-change model is that the γ subunit must rotate in one direction when FoF1 is synthesizing ATP and in the opposite direction whilst hydrolyzing ATP, was confirmed by the experiments of Masasuke Yoshida and Kazuhiko Kinosita, Jr.. In biological conditions, when the concentration of H+ ions for F0 motor is greater compared to F1 motor, protons enter the matrix through the F0 pore and the F0 motor rotates anticlockwise to turn around F1, thereby driving ATP synthesis. On the other hand, when the proton concentration is higher in the mitochondrial matrix, the F1 motor reverses the F0 motor bringing about the hydrolysis of ATP to power translocation of protons to the other side of membrane.
A team of Japanese scientists have succeeded in attaching magnetic beads to the stalks of F1-ATPase isolated in vitro, which rotated in presence of a rotating magnetic field. F1-ATPase synthesized ATP from ADP and Pi when rotated in a clockwise direction at a rate of about 5 molecules per second. Additionally, ATP was hydrolyzed when the stalks were rotated in the counterclockwise direction or when they were not rotated at all .
ATP Synthase Diseases
Defects or mutations in this enzyme are known to cause many diseases in humans. The first defect in ATP synthase was reported by Houstek et. al.in the case of a child with severe lactic acidosis, cardiomyopathy and hepatomegaly, who died 2 days after birth. Their study indicated that this enzyme was under expressed by 70-80% and there was no observed mutation or expression deficit in the enzyme. It was postulated that mutations in some factors explicitly involved in the assembly of ATP synthase could have caused the defect . Kucharczyk et. al.in their review have discussed mutations in both the nuclear and mitochondrial DNA. A mutation in one or many of the subunits in ATPase synthase can cause these diseases .
Mutation in α subunit has been associated with neuropathy, ataxia, retinitis pigmentosa syndrome, the familial bilateral striatal necrosis and one form of Leigh syndrome (neuromuscular disorder with a 50% survival rate to 3 year old children) [29, 30]. These diseases also result decrement in intermediary metabolism and functioning of the kidneys in removing acid from the body due to increased production of free oxygen radicals. A low expression of the β subunit and the cytosolic accumulation of the α subunit are known to cause Alzheimer’s disease. Dysfunction of F1 specific nuclear encoded assembly factors causes selective ATPase deficiency . Similar inborn defects in the mitochondrial F-ATP synthase, termed ATP synthase deficiency, have been noted where newborns die within few months or a year.
ATP Synthase Inhibition
Current research on ATP synthase as a potential molecular target for the treatment for some human diseases have produced positive consequences. Recently, ATPase has emerged as appealing molecular target for the development of new treatment options for several diseases. ATP synthase is regarded as one of the oldest and most conserved enzymes in the molecular world and it has a complex structure with the possibility of inhibition by a number of inhibitors. In addition, structure elucidation has opened new horizons for development of novel ATP synthase-directed agents with plausible therapeutic effects. More than 250 natural and synthetic inhibitors have been classified to date, with reports of their known or proposed inhibitory sites and modes of action .
We look to explore a few important inhibitors of ATP synthase in this paper. A drug, diarylquinoline (also known as TMC207) developed against tuberculosis is known to block the synthesis of ATP by targeting subunit c of ATP synthase of tuberculosis bacteria. Another such diarylquinone, Bedaquiline, is used for the treatment of multidrug resistant tuberculosis.
Among other ATP synthase inhibitors, Bz-423 is proapoptotic and 1,4-benzodiazepine binds the oligomycin sensitivity conferring protein (OSCP) component resulting in the generation of superoxide and subsequent apoptosis [32, 33, 34]. Melittin, a cationic, amphiphilic polypeptide is yet another ATP synthase inhibitor with documented inhibition of catalytic activities in mitochondrial and chloroplast ATP synthases .
IF1 and oligomycin are two other important classes of ATPase inhibitors. The binding of IF1, an endogenous inhibitor protein, fundamentally locks the ATP bound to the catalytic site of ATPase and restricts ATP hydrolysis. Oligomycin, an antibiotic, blocks protein channel F0 subunit and this inhibition eventually inhibits the electron transport chain. This further prevents protons from passing back into mitochondria, eventually ceasing the operations of the proton pump, as the gradients become too high for them to operate.
Several polyphenolic phytochemicals, such as quercetin and resveratrol, have been known to affect the activity ATPase. Resveratrol and Genistein are profound non-competitive inhibitors of F0F1-ATPase. Quercetin, a flavonoid, inhibits F-ATPase and other ATPases, such as Na+/K+-ATPase, Ca2+-ATPase. At decreased concentrations, it inhibits both soluble and insoluble mitochondrial ATPase. However, it does not impact oxidative phosphorylation occurring in other mitochondrial entities [39, 40, 41].
Several other plant products also serve as ATPase inhibitors. Polyphenols and flavones has been found effective in the inhibition of bovine and porcine heart F0F1-ATPase [41, 42]. Efrapeptins are peptides which are produced by fungi of the genus Tolypocladium that have antifungal, insecticidal and mitochondrial ATPase inhibitory activities . They target F1 particles, especially in the α, β and γ subunits, thereby inhibiting both ATP hydrolysis and ATP synthesis in mitochondria, chloroplasts, and photosynthetic bacteria. The mode of inhibition is competitive with ADP and phosphate . Another inhibitor piceatannol, a stilbenoid, has been found to inhibit the F-type ATPase preferably by targeting the F1 subunit .
Another inhibitor of ATPase is bicarbonate. Bicarbonate anion acts as activator of ATP hydrolysis and Lodeyro et. al.found that bicarbonate prompts ATP hydrolysis while inhibiting steady-state ATP synthesis profoundly by increasing the affinity of ATP for the catalytic site. This inhibition of ATP synthase activity was competitive with respect to ADP at low fixed phosphate concentration, mixed at high phosphate concentration and non-competitive towards Pi at any fixed ADP concentration .
Other inhibitors of ATPase are tenoxin, lecucinostatin, fluro-aluminate, dicyclohexyl-carbodimide and azide. Tentoxin, a phyotoxin, specifically inhibits the activity of chloroplast ATP synthases by binding at the cleft between the α and β subunits close to N-terminal beta-barrel crown of F1 . Leucinostatins bind to the F0 part of ATP synthases and inhibit oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts . Fluoroaluminate based inhibitors bind together with ADP in catalytic sites and freeze the enzyme in a confirmation that presumably reflects an intermediate step of ATP hydrolysis/synthesis . Dicyclohexylcarbodiimide (DCCD) reacts with the carboxyl group of the conserved acidic amino acid residue of subunit c at higher pH levels. However, at a lower pH (<7), DCCD modifies several carboxyl groups in F1 and inactivates it. So this compound can be considered as an inhibitor of both FO and F1. However, inhibition of FO is highly specific, well-defined, and requires a much lower concentration of the inhibitor . Azide in mitochondrial F1 selectively inhibits ATPase activity by binding with MgADP (interacting with its beta-phosphate) in a catalytic site, and presumably prevents ADP release from this site, leaving its ATP synthesis activity unaffected .
The list of inhibitors that directly and indirectly inhibit the activity of ATP synthase includes, magnesium, bismuth subcitrate and omeprazole, ethidium bromide, adenylyl imidodiphosphate, arsenate, angiostatin and enterostatin, ossamycin, dequalinium and methionine, almitrine, apoptolidin, aurovertin and citreoviridin, rhodamines, venturicidin, estrogens, catechins, kaempferol, genistein, biochanin A, daidzein and continues to grow [50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62].
Capaldi RA, Aggeler R, Turina P, Wilkens S. Coupling between catalytic sites and the proton channel in F1F0-type ATPases. Trends in biochemical sciences. 1994;19(7):284-289. CrossrefPubMedGoogle Scholar
Nijtmans LG, Klement P, Houštěk J, Van den Bogert C. Assembly of mitochondrial ATP synthase in cultured human cells: implications for mitochondrial diseases. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1995;1272(3):190-198. Google Scholar
Ahmad Z, Cox JL. ATP Synthase: The Right Size Base Model for Nanomotors in Nanomedicine. The Scientific World Journal. 2014; 2014:567398. Published 2014 Jan 29. Google Scholar
Rigoulet M, Mourier A, Devin A. Organization and Regulation of Mitochondrial Oxidative Phosphorylation. In Prof. Valdur Saks, Editor. Molecular System Bioenergetics: Energy for Life. New Jersey: John Wiley & Sons, Inc; 2007:29-58. Google Scholar
Schäfer G, Engelhard M, Müller V. Bioenergetics of the Archaea. Microbiology and Molecular Biology Reviews. 1999;63(3):570-620. Google Scholar
Nelson DL, Cox MM. Lehninger Principles of biochemistry.5th Ed. NewYork: WH Freeman and Company; 2008. Google Scholar
Feniouk BA. ATP Synthase FAQ. Web site. http://www.atpsynthase.info/FAQ.html Published 2012. Accessed March 26, 2018.
McCarty RE. A plant biochemist’s view of H+-ATPases and ATP synthases. Journal of Experimental Biology. 1992;172(1):431-441. Google Scholar
Masamitsu F, Mayumi N, Okamoto H, Sekiya M, Nakamoto RK. Rotational catalysis in proton pumping ATPases: From E. coli F-ATPase to mammalian V-ATPase. Biochimica et Biophysica Acta (BBA) – Bioenergetics. 2012;1817(10):1711-1721. CrossrefGoogle Scholar
Abrahams JP, Leslie AGW, Lutter R, Walker JE. Structure at 2.8 Â resolution of F1. Nature. 1994;64(2):10-12. Google Scholar
Duncan TM, Bulygin VV, Zhou Y, Hutcheon ML, Cross RL. Rotation of subunits during catalysis by Escherichia coli F1-ATPase. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(24):10964–10968. CrossrefPubMedGoogle Scholar
Houštek J, Klement P, Floryk D, Antonická H, Hermanská J, Kalous M, et al. A novel deficiency of mitochondrial ATPase of nuclear origin. Human molecular genetics. 1999;8(11):1967-1974. CrossrefPubMedGoogle Scholar
Kucharczyk R, Zick M, Bietenhader M, Rak M, Couplan E, Blondel M, et al. Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2009;1793(1):186-199. CrossrefGoogle Scholar
de Vries DD, van Engelen BG, Gabreëls FJ, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome. Annals of neurology. 1993;34(3):410-412. PubMedCrossrefGoogle Scholar
Hong S, Pedersen PL. ATP synthase and the actions of inhibitors utilized to study its roles in human health, disease, and other scientific areas. Microbiology and Molecular Biology Reviews. 2008;72(4):590-641. CrossrefGoogle Scholar
Houštěk J, Mráček T, Vojtıšková A, Zeman J. Mitochondrial diseases and ATPase defects of nuclear origin. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2004;1658(1-2):115-121. CrossrefGoogle Scholar
Johnson KM, Chen X, Boitano A, Swenson L, Opipari AW, Glick GD. Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. Chemistry & biology. 2005;12(4):485-496. PubMedCrossrefGoogle Scholar
Blatt NB, Bednarski, JJ, Warner RE, Leonetti F, Johnson KM, Boitano A, et al. Benzodiazepine-induced superoxide signalsB cell apoptosis: mechanistic insight and potential therapeutic utility. The Journal of clinical investigation. 2002; 110(8): 1123-1132. CrossrefPubMedGoogle Scholar
Blatt NB, Boitano AE, Lyssiotis CA, Opipari AW, Glick GD. Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax. Biochemical pharmacology. 2009;78(8):966-973. PubMedCrossrefGoogle Scholar
Datiles MJ, Johnson EA, McCarty RE. Inhibition of the ATPase activity of the catalytic portion of ATP synthases by cationic amphiphiles. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2008;1777(4):362-368. CrossrefGoogle Scholar
Cabezon E, Butler PJ, Runswick MJ, Carbajo RJ, Walker JE. Homologous and heterologous inhibitory effects of ATPase inhibitor proteins on F-ATPases. J. Biol. Chem. 2002;277:41334–41341. PubMedCrossrefGoogle Scholar
Pullman ME, Monroy GC. A Naturally Occurring Inhibitor of Mitochondrial Adenosine Triphosphatase. The Journal of Biological Chemistry. 1963;283(11):3762-3769. Google Scholar
Cabezón E, Montgomery MG, Leslie AG, Walker JE. The structure of bovine F1-ATPase in complex with its regulatory protein IF 1. Nature Structural and Molecular Biology. 2003;10(9):744-750. CrossrefGoogle Scholar
Fewtrell CMS, Gomperts BD. Quercetin: A novel inhibitors of Ca2+ influx and exocytosis in rat peritoneal mast cells. Biochimica et Biophysica Acta (BBA) – Biomembranes. 1977;469(1):52-60. CrossrefGoogle Scholar
Lang DR, Racker E. Effect of quercetin and F1 inhibitor on mitochondrial ATPase and energy-linked reactions in submitochondrial particles. Biochim. Biophys. Acta. 1974;333(2):180–186. PubMedCrossrefGoogle Scholar
Di Pietro A, Godinot C, Bouillant ML, Gautheron DC. Pig heart mitochondrial ATPase: properties of purified and membrane-bound enzyme: Effects of flavonoids. Biochemie. 1975;57(8):959–967. CrossrefGoogle Scholar
Krasnoff SB, Gupta S, Leger RJ, Renwick JAA, Roberts DW. Antifungal and insecticidal properties of the efrapeptins: Metabolites of the fungus Tolypocladium niveum. Journal of Invertebrate Pathology. 1991;58(2):180-188. CrossrefGoogle Scholar
Lodeyro A, Calcaterra N, Roveri O. Inhibition of steady-state mitochondrial ATP synthesis by bicarbonate, an activating anion of ATP hydrolysis. Biochimica et biophysica acta. 2001;1506(3):236-243. PubMedCrossrefGoogle Scholar
Yarlett N, Lloyd D. Effects of inhibitors on mitochondrial adenosine triphosphatase of Crithidia fasciculata: an unusual pattern of specificities. Molecular and Biochemical Parasitology. 1981;3(1):13–17. PubMedCrossrefGoogle Scholar
Feniouk BA, Skulachev VP. Cellular and Molecular Mechanisms of Action of Mitochondria-Targeted Antioxidants. Current aging science. 2016;10(1):41-48. Google Scholar
Weber J, Senior AE. Effects of the inhibitors azide, dicyclohexylcarbodiimide, and aurovertin on nucleotide binding to the three F1- ATPase catalytic sites measured using specific tryptophan probes. The Journal of Biological Chemistry. 1998;273:33210–33215. CrossrefPubMedGoogle Scholar
Bowler MW, Montgomery MG, Leslie AG, Walker JE. How azide inhibits ATP hydrolysis by the F-ATPases. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(23):8646-8649. CrossrefPubMedGoogle Scholar
Crosby B, Boutry M, Goffeau A. Inhibition of soluble yeast mitochondria ATPase by ethidium-bromide. Biochemical and Biophysical Research Communications. 1979;88(2):448–455. PubMedCrossrefGoogle Scholar
Mitchell RA, Chang BF, Huang CH, DeMaster EG. Inhibition of mitochondrial energy-linked functions by arsenate: Evidence for a non hydrolytic mode of inhibitor action. Biochemistry. 1971;10:2049–2054. CrossrefGoogle Scholar
Moser TL, Stack MS, Asplin, I, Enghild JJ, Hojrup P, Everitt L, et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl. Acad. Sci. 1999; 96:2811–2816. CrossrefGoogle Scholar
Ren HM, Allison WS, Photoinactivation of the F1-ATPase from spinach chloroplasts by dequalinium is accompanied by derivatization of methionine 183. J. Biol. Chem.1997; 272:32294–32300. CrossrefGoogle Scholar
Rigoulet M, Ouhabi R, Leverve X, Putod-Paramelle F, Guerin B. Almitrine, a new kind of energy-transduction inhibitor acting on mitochondrial ATP synthase. Biochim. Biophys. Acta. 1989;975:325–329. CrossrefPubMedGoogle Scholar
Wieker HJ, Kuschmitz D, Hess B. Inhibition of yeast mitochondrial F1-ATPase, F0F1-ATPase and submitochondrial particles by rhodamines and ethidium bromide. Biochim. Biophys. Acta.1987;892:108–117. PubMedCrossrefGoogle Scholar
Zheng J, Ramirez VD. Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na, K-ATPase of porcine cortex. Eur. J. Pharmacol. 1999;368:95– 102. PubMedGoogle Scholar
About the article
Published Online: 2019-03-07
Conflict of interest: Authors state no conflict of interest
Citation Information: Biomolecular Concepts, Volume 10, Issue 1, Pages 1–10, ISSN (Online) 1868-503X, ISSN (Print) 1868-5021, DOI: https://doi.org/10.1515/bmc-2019-0001.
© 2018 Prashant Neupane et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 Public License. BY 4.0