The F 0 part, bound to inner mitochondrial membrane is involved in proton translocation, whereas the F 1 part found in the mitochondrial matrix is the water soluble catalytic domain. F 1 is the first factor recognized and isolated from bovine heart mitochondria and is involved in oxidative phosphorylation.
F 0 was named so as it is a factor that conferred oligomycin sensitivity to soluble F 1 [ 18 ]. Schematic subunit composition of ATP synthase.
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. Bacterial F 0 has the simplest subunit structure consisting a 1 , b 2 and c subunits. Other additional subunits such as subunit e, f, g, and A6L extending over the membrane cohort with F 0 [ 5 , 10 , 20 ]. 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 [ 21 ].
The movement of subunits within the ATP synthase complex plays essential roles in both transport and catalytic mechanisms. 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.
The binding-change mechanism as seen from the top of the F 1 complex. There are three catalytic sites in three different conformations: loose, open, and tight.
As a result, ATP is released from the enzyme. In step 2, substrate again binds to the open site, and another ATP is synthesized at the tight site [ 25 ]. Masamitsu et. Conformational transitions that are significant in rotational catalysis are directed by the passage of protons through the F 0 assembly of ATP synthase. On the other hand, when the proton concentration is higher in the mitochondrial matrix, the F 1 motor reverses the F 0 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 F 1 -ATPase isolated in vitro , which rotated in presence of a rotating magnetic field. Additionally, ATP was hydrolyzed when the stalks were rotated in the counterclockwise direction or when they were not rotated at all [ 26 ]. 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. It was postulated that mutations in some factors explicitly involved in the assembly of ATP synthase could have caused the defect [ 27 ].
Kucharczyk et. A mutation in one or many of the subunits in ATPase synthase can cause these diseases [ 28 ]. 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.
Dysfunction of F 1 specific nuclear encoded assembly factors causes selective ATPase deficiency [ 31 ]. 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. 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 natural and synthetic inhibitors have been classified to date, with reports of their known or proposed inhibitory sites and modes of action [ 30 ].
We look to explore a few important inhibitors of ATP synthase in this paper. A drug, diarylquinoline also known as TMC 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 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 [ 35 ]. IF1 and oligomycin are two other important classes of ATPase inhibitors. Oligomycin, an antibiotic, blocks protein channel F 0 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. 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 ].
This scheme is based on the binding change mechanism of ATP hydrolysis [ 36 ]. IF1 is a naturally occurring 9. Several other plant products also serve as ATPase inhibitors. Polyphenols and flavones has been found effective in the inhibition of bovine and porcine heart F 0 F 1 -ATPase [ 41 , 42 ]. Efrapeptins are peptides which are produced by fungi of the genus Tolypocladium that have antifungal, insecticidal and mitochondrial ATPase inhibitory activities [ 43 ].
The mode of inhibition is competitive with ADP and phosphate [ 30 ]. Another inhibitor piceatannol, a stilbenoid, has been found to inhibit the F-type ATPase preferably by targeting the F 1 subunit [ 39 ].
Another inhibitor of ATPase is bicarbonate. Bicarbonate anion acts as activator of ATP hydrolysis and Lodeyro et. 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 [ 44 ].
Other inhibitors of ATPase are tenoxin, lecucinostatin, fluro-aluminate, dicyclohexyl-carbodimide and azide. Leucinostatins bind to the F 0 part of ATP synthases and inhibit oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts [ 46 ].
Dicyclohexylcarbodiimide DCCD reacts with the carboxyl group of the conserved acidic amino acid residue of subunit c at higher pH levels. So this compound can be considered as an inhibitor of both F O and F 1.
However, inhibition of F O is highly specific, well-defined, and requires a much lower concentration of the inhibitor [ 48 ]. 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 ].
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Human molecular genetics. Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Annals of neurology. The proton gradient results in a state where the intermembrane space is positive and acidic relative to the matrix.
The shorthand for this situation is: positive out, negative in; acidic out, basic in. Quantitatively, the energy gradient across the membrane is the sum of the energies due to these two components of the gradient:. The combination of the two components provides sufficient energy for ATP to be made by the multienzyme Complex V of the mitochondrion, more generally known as ATP synthase. See Figure 1. The mechanism of ATP synthase is not what one would naively predict.
This is borne out by two experimental observations: An artificial proton gradient can lead to ATP synthesis without electron transport, and molecules termed uncouplers can carry protons through the membrane, bypassing ATP synthase. In this case, the energy of metabolism is released as heat. One such uncoupler is the compound dinitrophenol, shown in Figure.
Dinitrophenol is a weak acid that is hydrophobic enough to be soluble in the inner membrane. It is protonated in the intermembrane space and deprotonated on the matrix side of the membrane. Because no ATP is made, energy from food is not available for fat synthesis. Indeed, dinitrophenol was used as a diet drug until side effects, including liver toxicity, led to its being withdrawn from the market.
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