Fact-checked by Grok 2 weeks ago

ATP synthase

ATP synthase is a rotary enzyme complex that catalyzes the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (P_i), powered by a proton gradient across cellular membranes.^[1] This molecular machine operates in reverse to hydrolyze ATP under certain conditions, but its primary biological role is ATP production during oxidative phosphorylation in mitochondria or photophosphorylation in chloroplasts.^[1] Found in the inner mitochondrial membrane of eukaryotes, the thylakoid membranes of chloroplasts, and the plasma membranes of bacteria, ATP synthase is essential for harnessing electrochemical energy to drive cellular metabolism.^[1] The enzyme comprises two functional domains: the membrane-embedded F_O sector, which forms a proton-translocating channel, and the soluble F₁ sector, which houses the catalytic sites for ATP synthesis.^[1] The F₁ portion consists of a hexameric α₃β₃ head with a central γ rotor, peripheral stator elements including the δ subunit, and the rotor ε subunit, while the F_O sector includes a ring of 8–17 c-subunits, an a-subunit proton channel, and b-subunit stator components that connect the two domains.^[1] The first high-resolution crystal structure of the bovine mitochondrial F₁-ATPase, revealing asymmetric catalytic sites, was determined in 1994 at 2.8 Å resolution.^[2] ATP synthase functions through a rotational mechanism proposed by Paul Boyer in the 1970s, known as the binding change mechanism, where proton flow through the F_O c-ring drives stepwise rotation of the γ rotor, inducing conformational changes in the β-subunits to sequentially bind substrates, form ATP, and release the product.^[3] This rotary catalysis couples proton translocation (typically 3–4 H⁺ per ATP) to energy conversion with near-perfect efficiency, making ATP synthase a cornerstone of bioenergetics.^[1] Cryo-EM structures, such as those of Escherichia coli ATP synthase at 3.1–3.4 Å resolution in 2020 and more recent ones from Thermus thermophilus in 2025, have illuminated intermediate rotational states and oligomeric assemblies (dimers, tetramers) that shape mitochondrial cristae morphology.^[4]^[5] Dysregulation of ATP synthase contributes to mitochondrial diseases and is a target for antimicrobial and anticancer drugs due to its conservation across species.^[1]

Fundamentals

Nomenclature

ATP synthase, specifically the F-type variant, is the predominant form responsible for ATP synthesis in mitochondria, chloroplasts, and bacterial plasma membranes, utilizing a proton-motive force to drive the reaction.^[6] It is distinguished from V-type ATPases, which primarily function in proton pumping for vacuolar acidification in eukaryotic endomembranes, and A-type ATPases, which occur in archaea and exhibit hybrid capabilities but are structurally more akin to V-type enzymes.^[7] These distinctions arise from evolutionary adaptations, with F-type enzymes optimized for energy conservation through synthesis, while V- and A-types emphasize ion translocation via hydrolysis.^[8] The term "ATP synthase" emphasizes its biosynthetic role, converting ADP and inorganic phosphate into ATP, whereas "F₁F_o-ATPase" highlights its historical identification as an ATPase capable of reversing this process under certain conditions.^[6] The "F" designation originates from "phosphorylation factor," reflecting its role in oxidative phosphorylation, with F₁ named for the first soluble fraction isolated from mitochondria and F_o (not "F0") for its sensitivity to oligomycin, an inhibitor of the membrane-embedded sector.^[7] Officially classified under Enzyme Commission number EC 7.1.2.2 as a translocase, its systematic name is ATP phosphohydrolase (H⁺-transporting), acknowledging its dual phosphohydrolase and proton-translocating activities.^[6] Classification of ATP synthases and related ATPases relies on subunit composition and operational modes, with F-type enzymes featuring a characteristic α₃β₃γδε catalytic core in the F₁ sector and an a b c-ring proton channel in the F_o sector, enabling efficient switching between synthesis (driven by proton flow) and hydrolysis (reversing proton pumping).^[7] In contrast, V-type ATPases incorporate additional peripheral stalks and subunits like d and C for robust proton pumping during hydrolysis, with limited synthesis capacity, while A-type variants share V-like subunits but adapt to archaeal membranes for bidirectional function.^[9] This nomenclature underscores functional versatility, as all types can theoretically operate in both modes, though F-type predominates in physiological ATP production.^[6]

Discovery and Historical Context

The understanding of ATP synthase emerged from decades of debate over the mechanism of oxidative phosphorylation, the process by which cells couple electron transport to ATP production. In the 1950s, prevailing theories favored direct chemical coupling, positing high-energy chemical intermediates that linked respiration to phosphorylation without invoking membrane potentials. This view, championed by researchers like David Keilin and E.C. Slater, contrasted with emerging evidence suggesting a role for proton gradients across membranes. A pivotal shift occurred in 1961 when Peter Mitchell proposed the chemiosmotic hypothesis, arguing that electron transport creates an electrochemical proton gradient across the inner mitochondrial membrane, which then drives ATP synthesis via a membrane-embedded enzyme. This theory resolved inconsistencies in prior models by emphasizing delocalized proton flow rather than localized chemical bonds, though it faced initial skepticism and required experimental validation. Mitchell's work earned him the 1978 Nobel Prize in Chemistry. Key experimental progress came from Ephraim Racker's group, who in 1960 isolated the soluble F1 portion of the ATP synthase from beef heart mitochondria, identifying it as an ATPase essential for oxidative phosphorylation.^[10] Building on this, Racker's team in the early 1970s reconstituted ATP synthesis by incorporating purified F1 and the membrane-bound F0 components into artificial liposomes, demonstrating that a proton gradient alone could power ATP formation.^[11] A landmark 1974 experiment paired bacterial ATP synthase with bacteriorhodopsin in liposomes, showing light-induced proton pumping directly drove ATP synthesis, decisively supporting Mitchell's hypothesis over chemical coupling models.^[12] Further elucidation of ATP synthase's structure came in the 1990s through John E. Walker's crystallographic studies, which revealed the enzyme's rotary architecture and subunit composition. Walker's 1994 determination of the F1 subunit's 2.8 Å structure confirmed three catalytic β-subunits arranged asymmetrically, providing a molecular basis for the binding change mechanism of ATP synthesis. This work, shared with Paul D. Boyer, earned Walker the 1997 Nobel Prize in Chemistry for clarifying the enzyme's mechanism.^[13]

Molecular Structure

F1 Subunit

The F1 subunit of ATP synthase is the peripheral, water-soluble domain responsible for the catalytic activity of ATP synthesis and hydrolysis. It comprises an α₃β₃ hexameric head, along with γ, δ, and ε subunits, in a stoichiometry of α₃β₃γδε. In bovine mitochondria, the mature subunits have approximate molecular weights of 55 kDa (α), 51 kDa (β), 30 kDa (γ), 15 kDa (δ), and 5.7 kDa (ε). The alternating α and β subunits form the catalytic core, where the three β subunits each bind nucleotides and house the active sites for ATP processing; the α subunits primarily provide structural support and non-catalytic nucleotide binding. The γ subunit serves as the central rotor element, asymmetrically interacting with the hexamer, while the δ and ε subunits form a base that connects to the membrane-embedded F₀ domain in the holoenzyme.^[14] Structurally, the α₃β₃ ring exhibits pseudosymmetry, with the three β subunits adopting distinct conformations—open (O), loose (L), and tight (T)—that reflect different stages of nucleotide binding and catalysis. This asymmetry arises from the off-center insertion of the elongated, coiled-coil γ subunit into the central cavity of the hexamer, which induces rotational strain and differential nucleotide affinities at the β sites. The crystal structure of bovine F₁-ATPase, resolved at 2.8 Å in 1994, first visualized this arrangement, showing the O-state β subunit empty, the L-state bound to ADP, and the T-state with tightly bound ATP, thereby illustrating the cooperative dynamics essential for function.^[2] Isolated F₁ was first purified as a soluble ATPase from bovine heart mitochondria in 1960 by Pullman, Penefsky, and Racker using urea stripping of submitochondrial particles followed by chromatography on Sephadex and hydroxylapatite columns. This preparation yielded a homogeneous protein with high hydrolytic activity toward ATP, insensitive to oligomycin but inhibited by azide and antibodies raised against it. Such isolates demonstrated that F₁ alone can hydrolyze ATP efficiently, providing early evidence of its catalytic autonomy, though in vivo ATP synthesis requires its attachment to F₀ for proton-driven rotation.

F0 Subunit

The F0 subunit of ATP synthase is the membrane-embedded portion that functions as a proton-translocating motor, embedded within the inner mitochondrial membrane in eukaryotes or the plasma membrane in prokaryotes. It consists of a rotating c-ring composed of multiple identical c-subunits, along with the stator components including the a-subunit, two copies of the b-subunit (b₂), and accessory subunits d, F6, and 8, which contribute to structural stability and assembly. In mammalian mitochondria, such as bovine heart, the c-ring typically comprises 8 c-subunits, while stoichiometry varies across organisms from 8 to 15 subunits, influencing the proton-to-ATP coupling ratio.^[9]^[14] Structurally, each c-subunit features two transmembrane α-helices arranged in a hairpin configuration, with a critical carboxylate residue (aspartate or glutamate) in the second helix that binds protons. The c-ring forms a cylindrical rotor that interacts intimately with the a-subunit, a multi-transmembrane protein with 6-8 helices depending on the species. At the a-c interface lies the proton wire, a pathway involving polar residues and water molecules that facilitates proton translocation without free diffusion across the lipid bilayer.^[15]^[14] The role of F0 in proton conduction relies on the electrochemical proton gradient (proton motive force) across the membrane, which drives protons through two half-channels in the a-subunit: an entry half-channel from the intermembrane space (or periplasm in bacteria) and an exit half-channel toward the matrix (or cytoplasm). Protons enter the entry channel, bind to the carboxylate on a c-subunit, inducing rotation of the c-ring as the protonated subunit moves away from a conserved arginine residue in the a-subunit; upon reaching the exit channel, the proton is released after deprotonation, completing the translocation cycle. This rotary motion generates torque transmitted via the central stalk to the F1 subunit for ATP synthesis. Stoichiometric variations in the c-ring, such as 10 subunits in yeast mitochondria or 14-15 in some chloroplasts, adjust the step size of rotation and energetic efficiency.^[15]^[14]

Overall Assembly and Dynamics

The ATP synthase complex assembles into a rotary molecular machine that spans the inner mitochondrial, bacterial plasma, or chloroplast thylakoid membrane, integrating the soluble F₁ domain with the membrane-embedded F_O domain through a central rotor and peripheral stator. The central rotor consists of the γ and ε subunits extending from the F₁ α₃β₃ hexamer to the oligomeric c-ring in F_O, enabling torque transmission across the membrane. The peripheral stator, formed by the dimeric b-subunits (b₂ in mitochondria), δ-subunit, and a-subunit, anchors the stationary α₃β₃ head and a-subunit to prevent co-rotation with the rotor during function.^[16]^[17] In membrane environments, ATP synthase oligomerizes into dimers primarily via F_O-F_O interactions at the c-ring and a-subunit interfaces, as revealed by cryo-EM structures of the yeast mitochondrial dimeric F_O at 3.6 Å resolution. These dimers further self-assemble into extended rows, imposing a local membrane curvature with a radius of approximately 17 nm, which is critical for shaping the tubular or lamellar architecture of mitochondrial cristae. In chloroplast thylakoids, ATP synthase adapts to the highly curved, stacked membrane domains through similar oligomeric arrangements, potentially including I-shaped dimers mediated by δ-subunit contacts, stabilizing the photosynthetic membrane folds.^[18]^[19]^[20] Dynamic structural studies using cryo-EM have elucidated the conformational flexibility underlying rotor-stator interactions during operation. High-resolution structures of the human mitochondrial ATP synthase, determined by cryo-EM in 2023, reveal three primary rotational states and one substate of the central rotor (γ-ε-c-ring), illustrating the conformational changes and flexibility in the peripheral stalk during rotation. The yeast dimeric F_O structure further demonstrates how lipid-embedded dimers maintain stability amid rotational dynamics, with the c-ring's hydrophobic interfaces enabling smooth pivoting against the a-subunit.^[16]^[18] Membrane interactions are mediated by specific lipid binding sites on the F_O components, including the c-ring's exterior grooves where cardiolipin and other phospholipids stabilize the oligomeric assembly. Cryo-EM of yeast ATP synthase reconstituted in lipid nanodiscs at 3.6 Å resolution identified multiple binding pockets for lipids and inhibitors like oligomycin on the c₁₀-ring surface, facilitating insertion into curved bilayers. In cristae, the angled dimer geometry generates negative curvature stress, promoting invagination, while in thylakoids, non-bilayer-prone lipids like monogalactosyldiacylglycerol enhance adaptation to the membrane's high curvature during light-induced stacking.^[21]^[22]^[23]

Mechanism of ATP Synthesis

Rotary Catalysis

The rotary catalysis of ATP synthase operates through a rotor-stator model, where the central rotor, consisting of the γ subunit in the F1 domain and the c-ring in the F0 domain, rotates relative to a stationary stator complex comprising the α3β3 hexamer, δ subunit, and peripheral stalk elements. This rotation is powered by proton translocation across the membrane via the F0 motor, generating torque that drives conformational changes in the catalytic sites of the F1 motor to synthesize ATP.^[24]^[25] The rotational mechanism proceeds in discrete 120° substeps per ATP molecule synthesized or hydrolyzed, with a full 360° rotation corresponding to the production of three ATP molecules, reflecting the three-fold symmetry of the F1 catalytic domain. Each 120° step is further subdivided into an 80° substep triggered by ATP binding and a 40° substep associated with phosphate release and catalytic dwell, enabling efficient energy coupling. The torque generated during rotation is approximately 40 pN·nm, sufficient to overcome frictional forces and drive continuous motion under physiological conditions.^[26]^[27]^[28] The proton-to-ATP stoichiometry, which determines the energetic efficiency of synthesis, varies based on the number of c-subunits in the rotor ring; in mammalian mitochondria, it is typically ~4 H⁺ per ATP (c-ring translocation of 8/3 H⁺ for the c₈ ring plus ~1 H⁺ for phosphate import). Recent engineering studies have demonstrated the adjustability of this ratio by modifying the c-ring composition, potentially enhancing efficiency in synthetic systems.^[29]^[30] Single-molecule biophysical studies have provided direct evidence for elastic power transmission between the F0 and F1 motors, where the flexible central stalk acts as a torsion spring to buffer discrete proton-driven steps in the c-ring, ensuring smooth 120° rotations in F1 despite the mismatch in step sizes. The structural basis for this rotary motion in F0 involves the sequential protonation and deprotonation of c-subunits, propelling the ring's rotation against the stator-embedded a-subunit channel.^[31]^[26]

Binding Change Mechanism

The binding change mechanism, proposed by Paul D. Boyer in the 1970s and recognized with the 1997 Nobel Prize in Chemistry, posits that ATP synthesis by ATP synthase occurs through sequential conformational alterations in the enzyme's catalytic sites, rather than direct enzymatic catalysis of the chemical bond formation. This model emphasizes cooperative interactions among the three β-subunits in the F1 domain, where energy from proton translocation induces binding affinity changes that drive the overall reaction forward.^[32] In Boyer's framework, each of the three catalytic sites cycles through distinct conformational states designated as open (O), loose (L), and tight (T), operating in a coordinated manner to synthesize and release ATP. The O state exhibits low nucleotide affinity, facilitating the release of newly formed ATP into solution. The L state allows initial, relatively weak binding of ADP and inorganic phosphate (Pi). Transition to the T state promotes tight binding and condensation of ADP and Pi into ATP, with the equilibrium strongly favoring product formation due to enhanced interactions at this conformation. These states interconvert sequentially as the sites rotate positions relative to the central γ-subunit. The core chemical reaction underlying synthesis is the reversible equilibrium:

\text{ADP} + \text{P}_\text{i} \rightleftharpoons \text{ATP}

This equilibrium is near unity under physiological conditions without energy input, but rotation of the γ-subunit—powered by the proton motive force—induces the binding changes that shift the process by lowering affinity in the O state to release ATP and raising it in the T state to form it tightly bound.^[32] In the T state, the dissociation constant (Kd) for ATP is approximately $10^{-12} M, reflecting its exceptionally high binding affinity and explaining why energy is primarily required for product release rather than synthesis.^[33] This rotational catalysis ensures efficient, unidirectional ATP production across the enzyme's sites.

Physiological Roles

In Cellular Respiration

In cellular respiration, ATP synthase plays a central role in oxidative phosphorylation, harnessing the proton motive force generated across the inner mitochondrial membrane in eukaryotes or the plasma membrane in prokaryotes to produce ATP. The electron transport chain (ETC) complexes I, III, and IV sequentially transfer electrons from reduced carriers like NADH and FADH₂ to oxygen, pumping protons into the intermembrane space and establishing an electrochemical gradient. This gradient, with Complex IV (cytochrome c oxidase) contributing significantly to proton extrusion, drives protons back through the F₀ subunit of ATP synthase, inducing conformational changes in the F₁ domain to catalyze ATP synthesis from ADP and inorganic phosphate. Oxidative phosphorylation via ATP synthase accounts for approximately 90% of cellular ATP production under aerobic conditions in most eukaryotic cells.^[34]^[35]^[34] The stoichiometry of proton translocation by ATP synthase is critical for the efficiency of ATP yield in respiration. In mammalian mitochondria, the c-ring of the F₀ subunit consists of eight c-subunits, resulting in a H⁺/ATP ratio of approximately 8/3 ≈ 2.67 protons translocated per ATP synthesized by the catalytic sites, though effective ratios are often cited as 2.5-3 H⁺/ATP when considering kinetic factors. In bacteria, the c-ring size varies (typically 10-15 subunits), leading to H⁺/ATP ratios of 3.3-5, but the principle of proton-driven rotary catalysis remains conserved. For the complete oxidation of glucose in mammalian cells—via glycolysis yielding 2 ATP and 2 NADH, the tricarboxylic acid cycle producing additional NADH and FADH₂, and subsequent ETC coupling—the net ATP yield is approximately 30-32 molecules per glucose, with oxidative phosphorylation contributing the majority.^[36]^[9]^[37] Under hypoxic or anoxic conditions, when ETC activity diminishes and the proton gradient collapses, ATP synthase can reverse its function, hydrolyzing ATP to pump protons outward and sustain mitochondrial membrane potential, thereby preventing excessive reactive oxygen species production and supporting cell survival until oxygen is restored. This reverse mode highlights the enzyme's bidirectional capability, enabled by its rotary mechanism, and is particularly relevant in bacterial anaerobiosis or mammalian ischemia. Inhibitory proteins like IF₁ in mitochondria regulate this reversal to minimize futile ATP consumption.^[38]^[39]^[40]

In Photosynthesis

In photosynthesis, ATP synthase embedded in the thylakoid membranes of chloroplasts harnesses the proton motive force generated by light-driven electron transport to produce ATP, essential for the subsequent carbon fixation in the Calvin cycle.^[41] The enzyme, denoted as CF₁-CF₀ in plants, operates similarly to its mitochondrial counterpart in utilizing rotary catalysis to synthesize ATP from ADP and inorganic phosphate.^[42] The proton gradient driving CF₁-CF₀ activity arises primarily from the light-dependent reactions involving photosystems I (PSI) and II (PSII). In non-cyclic electron flow, light absorption by PSII initiates water splitting, releasing protons into the thylakoid lumen and providing electrons that pass through the cytochrome b₆f complex to PSI, further translocating protons across the membrane via a Q-cycle mechanism.^[41] Cyclic electron flow, involving only PSI and ferredoxin, generates additional protons without net NADPH production, helping balance ATP/NADPH ratios needed for the Calvin cycle.^[43] This electrochemical gradient, with protons flowing back through the CF₀ subunit's c-ring (comprising 14 subunits in plants), rotates the rotor to drive conformational changes in the CF₁ catalytic sites for ATP synthesis.^[41] Plant-specific adaptations ensure efficient regulation of CF₁-CF₀ under varying light conditions. The ε subunit's C-terminal domain adopts an inhibitory conformation in the dark or low proton motive force, binding to the γ subunit to block ATP hydrolysis and prevent wasteful reversal of the enzyme.^[33] Additionally, redox modulation via thioredoxin reduces disulfide bonds on the γ subunit in the light, activating the enzyme and enhancing proton translocation efficiency.^[42] The stoichiometry of ATP production in chloroplasts yields approximately 4 H⁺ per ATP synthesized, determined by the 14-proton c-ring rotation producing 3 ATP molecules, which optimizes energy conversion under fluctuating light intensities.^[44] This ATP supply is critical for powering the Calvin cycle, where it drives phosphorylation reactions in carbon assimilation, sustaining photosynthetic productivity.^[41]

Distribution and Variations

In Prokaryotes

In bacteria, the F-type ATP synthase (F₀F₁) is embedded in the plasma membrane, where it harnesses the proton motive force generated by respiratory chains to synthesize ATP. The F₀ sector forms a proton-translocating rotor composed of a variable number (typically 10–15) of c-subunits arranged in a ring, which rotates relative to the stationary a-subunit to drive conformational changes in the soluble F₁ sector.^[45]^[46] A well-studied example is the ATP synthase in Escherichia coli, encoded by the atp operon at 83.2 min on the chromosome, which includes genes for eight core subunits (atpBEFHAGCD) transcribed in a counterclockwise direction from a promoter region.^[47] Recent cryo-EM structures of bacterial ATP synthase from the thermotolerant Thermus thermophilus, resolved at 2.2–3 Å in 2025, reveal dynamic rotational states during proton-powered ATP synthesis, highlighting adaptations for stability under elevated temperatures.^[5] In archaea, the analogous A-type ATP synthase (A₁A₀) shares a rotary mechanism but exhibits distinct structural features, including a collar-like assembly at the A₁-A₀ interface, an extended central stalk, and two peripheral stalks for enhanced rotational stability. The A₀ stator includes a unique a-subunit that differs from its bacterial counterpart in sequence and ion coordination, facilitating proton or sodium translocation through a c-ring typically comprising 10 subunits.^[48]^[49] These enzymes demonstrate higher thermotolerance, as exemplified by the A₁A₀ complex from the hyperthermophilic archaeon Pyrococcus furiosus, which maintains functionality at temperatures exceeding 100°C and features a 730 kDa assembly with A₃B₃CDE₂FH₂ac₁₀ stoichiometry, as determined by electron microscopy and mass spectrometry in 2009.^[49] Prokaryotic ATP synthases exhibit functional adaptations that couple ATP synthesis to diverse respiratory processes, including anaerobic pathways where ion gradients are generated by alternative electron acceptors like nitrate or sulfate. Variable c-ring stoichiometry, ranging from 10 in E. coli to 15 in certain cyanobacteria, modulates the H⁺/ATP ratio (n/3, where n is the number of c-subunits), optimizing energetic efficiency under fluctuating environmental conditions such as pH extremes or low proton motive force.^[50]^[46] This variability reflects evolutionary conservation from the last universal common ancestor (LUCA), where a minimal rotary ATPase likely enabled primitive energy conservation in prokaryotic membranes.^[46]

In Eukaryotes

In eukaryotic cells, ATP synthase is primarily localized to the inner membranes of mitochondria and chloroplasts, reflecting the compartmentalized nature of energy production in these organelles. The mitochondrial F_oF₁-ATP synthase consists of 17-18 subunits, the majority of which are encoded by nuclear genes, synthesized in the cytosol, and imported into the mitochondrial matrix via the TOM (translocase of the outer membrane) and TIM23 (translocase of the inner membrane) complexes. This import process involves recognition of N-terminal mitochondrial targeting signals by the TOM complex, followed by translocation across the inner membrane in an ATP- and membrane potential-dependent manner facilitated by TIM23.^[51] Among these nuclear-encoded components is the ATPase inhibitory factor 1 (IF1), a regulatory protein that binds to the F₁ domain to prevent ATP hydrolysis under conditions of low proton motive force, thereby stabilizing mitochondrial function; IF1 is translated as a precursor and processed upon import into the matrix.^[52] The F_o sector's c-ring, which translocates protons to drive rotation, typically comprises 8-10 identical c-subunits in mitochondrial ATP synthase across eukaryotes, with 8 in mammals and 10 in yeast, influencing the H⁺/ATP stoichiometry.^[53] In chloroplasts, the CF_oCF₁-ATP synthase exhibits a dual genetic origin, with key subunits encoded by both nuclear and plastid genomes to coordinate assembly and regulation with photosynthetic activity. The CF₁ sector's α, β, and ε subunits are transcribed from plastid genes (atpA, atpB, atpE), while γ and δ are nuclear-encoded and imported from the cytosol; similarly, the CF_o sector includes plastid-encoded subunits I and IV alongside nuclear-encoded components such as II and III. This bipartite encoding ensures stoichiometric balance through intertwined translational controls, preventing excess accumulation of individual subunits. A distinctive feature is redox regulation, where thioredoxin-f, reduced by the light-dependent ferredoxin-thioredoxin system, targets a disulfide bridge on the γ-subunit's C-terminal extension, activating the enzyme in illuminated conditions and deactivating it in the dark to conserve ATP.^[54]^[55] In fungi and yeast, such as Saccharomyces cerevisiae, ATP synthase adopts a dimeric organization within the inner mitochondrial membrane, forming extended rows along cristae ridges that actively contribute to membrane curvature and cristae formation. This dimerization, mediated by interactions between F_o subunits such as subunit e and the f-subunit, generates local membrane bending essential for efficient respiratory chain packing and proton gradient maintenance; disruptions in dimer formation lead to aberrant cristae morphology and impaired respiration.^[56] Across eukaryotic species, c-ring size varies (e.g., 8-15 subunits), adapting the enzyme's gearing ratio to physiological proton gradients in different organelles or lineages.^[8]

Specialized Forms

In the phylum Euglenozoa, mitochondrial ATP synthase forms a highly divergent dimer with a narrow 45° angle between monomers, as resolved by cryo-electron microscopy at 3.2 Å resolution in 2019; this V-shaped configuration relies on phylum-specific subunits for dimerization and includes unique extensions that stabilize the structure under varying membrane conditions.^[57] This atypical dimer contrasts with the wider angles (~90°) in most eukaryotic ATP synthases and supports specialized cristae morphology in these organisms.^[58] Chloroplast ATP synthases in algae, such as those in cyanobacteria-derived lineages, feature c-rings composed of 14 to 15 subunits, an adaptation that elevates the H⁺/ATP stoichiometry to approximately 4.7 and enables robust ATP production despite the relatively low proton motive force generated during oxygenic photosynthesis in thylakoid membranes.^[59] This gearing optimizes energy efficiency in light-limited or fluctuating environments, where the electrochemical gradient may not exceed 50-60 mV.^[60] In plant mitochondria, ATP synthase assembly involves dual targeting of specific subunits and factors, such as Atp11, to both mitochondria and chloroplasts via ambiguous N-terminal presequences, ensuring coordinated regulation of oxidative phosphorylation and photophosphorylation across organelles.^[61] This dual localization facilitates shared chaperone functions and maintains bioenergetic balance during stress responses like high light or drought.^[62] Trypanosome ATP synthase, found in the parasitic protist Trypanosoma brucei (also Euglenozoa), possesses a unique stator comprising an elaborated peripheral stalk with supernumerary subunits that compensate for the absence of the conserved subunit f, providing mechanical stability during reverse operation to maintain mitochondrial membrane potential in kinetoplastid parasites.^[63] Structural analyses reveal this stator's extended architecture, which includes novel transmembrane elements, enabling function in ATP hydrolysis mode under anaerobic conditions typical of the parasite's bloodstream stage.^[64] Recent bioengineering studies in 2025 have developed synthetic ATP synthase variants with enhanced efficiency, achieving H⁺/ATP ratios up to 5.8—nearly double the typical 3-4 in natural F-type enzymes—by incorporating multiple peripheral stalks to amplify torque generation and sustain synthesis at proton motive forces as low as 100 mV.^[30] These modifications, tested in reconstituted liposomes, highlight potential applications in synthetic biology for low-energy environments.^[65]

Evolution

Ancestral Origins

The ATP synthase complex is reconstructed to have been present in the last universal common ancestor (LUCA), approximately 4.2 billion years ago, as a core F-type enzyme driven by proton translocation across membranes. Phylogenetic analyses indicate that LUCA possessed both F-type and A/V-type ATP synthases, with the catalytic (β-like) and non-catalytic (α-like) subunits of the F₁ head already diverged through an ancient duplication event prior to this ancestor. The rotor ring in this ancestral form is often inferred to consist of 12 c-subunits, enabling a typical proton-to-ATP stoichiometry of about 4:1. Pre-LUCA origins remain speculative and minimal, with limited hypotheses linking the enzyme to an RNA world where nucleotide-based energy carriers might have preceded proteinaceous rotary mechanisms, though no direct evidence supports such transitions.^[66]^[67]^[68] The α and β subunits of the catalytic domain trace their origins to gene duplication of an ancient P-loop nucleoside triphosphatase (NTPase), likely a RecA-family protein with GTPase-like activity, where one paralog retained nucleotide hydrolysis capability while the other evolved regulatory functions. This duplication occurred before LUCA, establishing the asymmetric hexameric structure essential for the binding change mechanism. Independently, the membrane-embedded c-subunit, forming the proton-translocating rotor, is believed to have evolved from an ancient ion antiporter protein, adapting hairpin transmembrane helices for cooperative ion binding and ring rotation. These origins highlight ATP synthase as one of the most ancient molecular machines, predating the divergence of bacterial and archaeal lineages.^[66]^[69] Fossil evidence correlates the emergence of ATP synthase-dependent bioenergetics with early life forms around 3.5 billion years ago, as evidenced by microbial mats in ancient stromatolites from the Pilbara Craton. This timeline aligns with the hypothesis that primordial ATP synthases functioned in alkaline hydrothermal vents, harnessing natural geochemical proton gradients across thin inorganic barriers—such as FeS precipitates—for ATP synthesis without the need for complex respiratory chains. In these environments, the proton-driven F-type core would have provided a selective advantage for the transition from geochemical to biochemical energy conservation. This ancestral design remains highly conserved across modern prokaryotes, underscoring its fundamental role in cellular metabolism.^[67]^[70]

Evolutionary Adaptations

The c-ring of ATP synthase, a critical component of the rotor in the F_O domain, exhibits significant variation in subunit stoichiometry across evolutionary lineages, ranging from 8 to 15 subunits. This variability influences the ion-to-ATP coupling ratio (n/3, where n is the number of c-subunits), allowing adaptation to differing proton motive force (pmf) conditions, including the balance between ΔpH and Δψ components of the electrochemical gradient. In alkaliphilic bacteria such as Bacillus pseudofirmus, a larger c-ring with 13 subunits facilitates ATP synthesis under low pmf environments, where reduced ΔpH at high external pH necessitates higher ion translocation per ATP molecule for thermodynamic feasibility. Conversely, smaller c-rings, such as the 10-subunit ring in some neutralophilic bacteria like Bacillus PS3, support efficient operation in higher pmf settings, optimizing energy conversion for rapid growth. These adaptations likely arose post-LUCA through selective pressures on the conserved GxGxGxG motif in c-subunits, enabling fine-tuning of rotary mechanics to physiological demands.^[71]^[46]^[71] The divergence of V- and A-type ATPases from the ancestral F-type core occurred prior to LUCA, approximately 4.5 billion years ago, as inferred from recent phylogenetic analyses. This split involved gene duplication events, particularly of nucleotide-binding domains, with subsequent losses of function in duplicated genes refining efficiency. V-type ATPases, prevalent in eukaryotes, evolved primarily as proton-pumping hydrolytic enzymes, reversing the synthetic role of F-type synthases while retaining rotary architecture; A-type variants in archaea show intermediate features. These changes reflect selective pressures for compartmentalization in eukaryotic endomembranes, building on the primordial F-type mechanism present in the last universal common ancestor.^[66]^[46]^[72] Recent studies highlight energetics constraints shaping these adaptations, with c-ring stoichiometry directly impacting the free energy span for ATP synthesis (typically -43 to -61 kJ/mol across taxa), ensuring reversibility under varying pmf. A 2020 review emphasizes how such constraints drove post-LUCA diversification to balance synthesis efficiency against ion leakage risks. Concurrently, membrane lipids co-evolved with ATP synthase, particularly cardiolipin in bacterial and mitochondrial membranes, which stabilizes dimer formation, enhances rotor torque, and promotes cristae curvature for increased surface area and pmf generation. This lipid-protein interplay, conserved across domains, underscores efficiency gains in energy transduction without altering core rotary principles.^[46]^[73]

Inhibitors and Therapeutic Implications

Known Inhibitors

Oligomycin is a well-known inhibitor of ATP synthase that specifically binds to the c-subunit within the F_O sector, thereby blocking proton translocation through the membrane and halting the rotary mechanism essential for ATP synthesis.^[74] Analogs such as venturicidin similarly target the c-subunit ring in F_O, inhibiting both proton flow and ATPase activity by occupying overlapping binding pockets and preventing the conformational changes required for rotation.^[74] Aurovertin, another fungal-derived inhibitor, acts as an uncompetitive antagonist by binding to the β-subunit in the F_1 sector, which disrupts ATP hydrolysis more potently than synthesis and interferes with the enzyme's catalytic dwell states.^[74] The physiological inhibitor IF1, also known as ATPase inhibitory factor 1, is an endogenous protein in mitochondria that binds to the interface between the α_DP and β_DP subunits in the F_1 sector in a pH-dependent manner, with binding affinity increasing below neutral pH to prevent wasteful ATP hydrolysis during ischemic conditions without affecting forward synthesis.^[75] Unlike chemical inhibitors, IF1's action is reversible and regulated by mitochondrial matrix pH, allowing dynamic control of enzyme activity.^[75] Many ATP synthase inhibitors exhibit antibacterial properties by disrupting energy metabolism in prokaryotes, where oligomycin and venturicidin effectively target bacterial F_O sectors to inhibit growth in pathogens like Staphylococcus aureus.^[76] However, their clinical utility is limited by toxicity profiles, including nephrotoxicity from oligomycin and aurovertin, which arises from off-target accumulation in renal cells leading to mitochondrial dysfunction and acute kidney injury.^[74] Recent structural analyses highlight distinct binding sites—such as the oligomycin pocket in the c-subunit helix—for designing less toxic variants, though challenges persist due to conserved residues across species.^[74]

Clinical Relevance and Diseases

Mutations in the MT-ATP6 gene, which encodes the ATP synthase subunit 6, are a primary cause of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by neurological and visual impairments due to impaired ATP production. The most common mutation, m.8993T>G, leads to a substitution of arginine for leucine at position 156 (L156R) in the subunit, disrupting the proton translocation function of the F_O domain and reducing ATP synthase activity by up to 70% in affected tissues. This heteroplasmic mutation's severity correlates with its heteroplasmy level, with loads above 80-90% often progressing to Leigh syndrome, a more severe encephalomyopathy.^[77]^[78] Mutations in the nuclear-encoded ATP5F1E gene, which produces the ε-subunit of the ATP synthase central stalk, have been linked to mitochondrial diseases with neuromuscular features overlapping amyotrophic lateral sclerosis (ALS), including progressive muscle weakness and motor neuron degeneration due to defective enzyme assembly and reduced oxidative phosphorylation. These rare variants impair the regulatory role of the ε-subunit in modulating ATP synthesis and hydrolysis, contributing to bioenergetic failure observed in ALS models where ATP synthase dysfunction exacerbates mitochondrial fragmentation and oxidative stress in motor neurons.^[79]^[80] In Alzheimer's disease (AD), ATP synthase β-subunit activity is significantly reduced in affected brain regions, correlating with cognitive decline and neuronal loss, as evidenced by decreased protein levels and impaired enzyme function in postmortem hippocampal tissues. Amyloid-β peptides directly inhibit ATP synthase by binding to the β-subunit, blocking its catalytic sites and diminishing ATP output by 30-50%, thereby promoting mitochondrial dysfunction and amyloid plaque formation in a vicious cycle. A 2020 review synthesizes these findings, highlighting ATP synthase as a key mitochondrial target in AD pathogenesis. Recent studies, including a 2025 analysis, have identified altered ATP synthase abundance in neuronal extracellular vesicles (NEVs) as a potential biomarker for AD by reflecting mitochondrial changes in parent neurons.^[81]^[82]^[83]^[84] Therapeutically, ATP synthase inhibitors like oligomycin are being repurposed to target the Warburg effect in cancer, where elevated glycolysis supports tumor proliferation; by blocking oxidative phosphorylation, these agents reduce ATP supply in glycolytic cancer cells, inducing apoptosis without severely affecting normal tissues. For mitochondrial diseases involving ATP synthase deficiencies, such as NARP, emerging research explores potential activators to enhance residual enzyme activity, including small molecules that stabilize the F_1 domain or promote subunit assembly, though clinical translation remains limited by specificity challenges.^[85]^[86]

References

[1]
ATP synthase FOF1 structure, function, and structure-based drug ...
The main functions of ATP synthases are control of the ATP synthesis and transmembrane potential. Although the key subunits of the enzyme remain highly ...
[2]
Structure at 2.8 Â resolution of F1-ATPase from bovine ... - Nature
Aug 25, 1994 · In the crystal structure of bovine mitochondrial F 1 -ATPase determined at 2.8 Å resolution, the three catalytic β-subunits differ in conformation and in the ...
[3]
[PDF] Paul D. Boyer - Nobel Lecture
During net ATP synthesis the three catalytic sites on the enzyme, acting in sequence, first bind ADP and phosphate, then undergo a conformational change so as ...
[4]
Cryo-EM structures provide insight into how E. coli F1Fo ATP ...
May 26, 2020 · F1Fo ATP synthase functions as a biological rotary generator that makes a major contribution to cellular energy production.
[5]
EC 7.1.2.2 - IUBMB Nomenclature
The F-type enzymes of the inner mitochondrial and thylakoid membranes act as ATP synthases. All of the enzymes included here operate in a rotational mode, where ...
[6]
Detailed information about the enzyme - ATP Synthase (FoF1-complex)
Differences between F-, A-, V-, P-, and E-ATPases. "F-type ATPase" is just another name for ATP synthase; letter "F" comes from "phosphorylation Factor". F ...
[7]
ATP synthase: Evolution, energetics, and membrane interactions
Sep 23, 2020 · The ATP synthase family of enzymes comprises three members: A-, V-, and F-type ATPases/ATP synthases (Kagawa and Racker, 1966; Penefsky et al., ...Missing: nomenclature | Show results with:nomenclature
[8]
Mitochondrial ATP synthase: architecture, function and pathology
F-type ATP synthases contain only one peripheral stalk, while A- and V-ATPases have two and three peripheral stalks, respectively, each made of an E-G ...Missing: nomenclature | Show results with:nomenclature
[9]
Press release: The 1997 Nobel Prize in Chemistry - NobelPrize.org
In 1960 the American scientist Efraim Racker and co-workers isolated, from mitochondria, the enzyme “F o F 1 ATPase” which we now call ATP synthase. The ...
[10]
Understanding structure, function, and mutations in the ...
This review will discuss the structure/function relationship in the ATP synthase as determined by biochemical, crystallographic, and genetic studies.
[11]
Structure of a bacterial ATP synthase - PMC - PubMed Central
Adenosine triphosphate (ATP) synthases are multi-subunit protein complexes that use an electrochemical proton motive force across a membrane to make the cell's ...
[12]
https://www.jbc.org/content/249/2/662
[13]
Structural organization of mitochondrial ATP synthase - ScienceDirect
The rotor is made up of the central stalk and the c-ring. The remainder of the subunits is assigned to the stator. (B) Dimer ribbons of mammalian ATP synthase ( ...
[14]
Atomic model for the dimeric FO region of mitochondrial ATP synthase
Oct 26, 2017 · Synthesis of adenosine triphosphate (ATP) in mitochondria is accomplished by a large molecular machine, the F1FO ATP synthase.Missing: F0 | Show results with:F0
[15]
Dimer ribbons of ATP synthase shape the inner mitochondrial ...
The dimer ribbons enforce a strong local curvature on the membrane with a 17‐nm outer radius. Calculations of the electrostatic field strength indicate a ...<|separator|>
[16]
I-Shaped Dimers of a Plant Chloroplast FOF1-ATP Synthase in ...
Concerning physiological relevance, we hypothesize that an I-shaped type of dimerization might stabilize the stacks of thylakoid membrane areas by the possible ...
[17]
Structures of rotary ATP synthase from Thermus thermophilus during ...
Oct 17, 2025 · The rotation of the DFdc12 by proton motive force (pmf) leads to a conformational change in the three AB dimers, resulting in the synthesis of ...
[18]
High-resolution cryo-EM analysis of the yeast ATP synthase in a lipid membrane
### Publication Details
[19]
Dimers of mitochondrial ATP synthase induce membrane curvature ...
Feb 13, 2019 · Molecular simulations have suggested that ATP synthase dimer rows bend the membrane locally, and that the induced membrane curvature promotes ...
[20]
Structural and functional roles of non-bilayer lipid phases of ...
In this review, we focus on structural and functional roles of non-bilayer lipids and non-bilayer (or non-lamellar) lipid phases of chloroplast thylakoid ...Review · 4. Structural Roles Of... · Appendix A. Supplementary...
[21]
The Rotary Mechanism of the ATP Synthase - PMC - PubMed Central
This review addresses the role of rotation in catalysis of ATP synthesis/hydrolysis and the transport of protons or sodium.
[22]
F1FO ATP synthase molecular motor mechanisms - PubMed Central
The F-ATP synthase, consisting of F1 and FO motors connected by a central rotor and the stators, is the enzyme responsible for synthesizing the majority of ATP ...
[23]
ATP synthase: from single molecule to human bioenergetics - PMC
The F1 reported by Racker's laboratory was not sensitive to an energy transfer inhibitor of oxphos, oligomycin, but became oligomycin sensitive when bound to F1 ...
[24]
How Does F1-ATPase Generate Torque?: Analysis From Cryo ...
The unitary rotation step is 120° rotation, which is divided into 80° and 40° substeps, initiated after the binding dwell and catalytic dwell, respectively; TF1 ...
[25]
Simple mechanism whereby the F1-ATPase motor rotates with near ...
F 1 -ATPase is a motor enzyme in which a central shaft γ subunit rotates 120° per ATP in the cylinder made of α 3 β 3 subunits.
[26]
The thermodynamic H+/ATP ratios of the H+-ATPsynthases from ...
The H+/ATP ratio is an important parameter for the energy balance of all cells and for the coupling mechanism between proton transport and ATP synthesis.
[27]
Engineering of ATP synthase for enhancement of proton-to-ATP ratio
Jul 3, 2025 · In this study, we seek to significantly enhance the H + /ATP ratio by employing an alternative approach that differs from that of nature.
[28]
Two rotary motors in F-ATP synthase are elastically coupled by a ...
Elastic power transmission between FO and F1 is essential for smoothing the cooperation of these stepping motors, thereby increasing their kinetic efficiency. A ...
[29]
The binding change mechanism for ATP synthase - PubMed - NIH
The binding change mechanism for ATP synthase--some probabilities and possibilities. Biochim Biophys Acta. 1993 Jan 8;1140(3):215-50. doi: ...Missing: original | Show results with:original
[30]
Review Important subunit interactions in the chloroplast ATP synthase
Incubation of the mitochondrial F1 with sub-stoichiometric amounts of substrate MgATP leads to its very tight binding (dissociation constant of <10−12M) and ...Missing: Kd | Show results with:Kd
[31]
Variation in the link between oxygen consumption and ATP ...
The majority of ATP is produced via oxidative phosphorylation, a process through which substrate molecules are first oxidized by the tricarboxylic acid cycle ...
[32]
Mitochondrial dysfunction: mechanisms and advances in therapy
May 15, 2024 · ... mitochondrial matrix through ATP synthase, thereby coupling electron transport with oxidative phosphorylation. Integral to this process ...
[33]
ATP synthase: From sequence to ring size to the P/O ratio - PNAS
Sep 21, 2010 · P/O is the number of ATP molecules synthesized by oxidative phosphorylation for each pair of electrons (hence, not P/O 2 ) passing from a particular substrate.
[34]
Quantifying intracellular rates of glycolytic and oxidative ATP ...
Complete oxidation of glucose by cells yields up to 33.45 ATP/glucose with a maximum P/O of 2.79. We introduce novel indices to quantify bioenergetic phenotypes ...
[35]
Inhibition of ATP synthase reverse activity restores energy ...
Inhibition of ATP hydrolysis, alone, is sufficient to prevent ATP depletion, restore cellular function and improve muscle strength in model of Duchenne ...
[36]
The new role of F1Fo ATP synthase in mitochondria-mediated ...
The F1 subdomain consists of subunits α, β, γ, δ, ε and the regulatory protein IF1, which are located in the mitochondrial matrix. The three copies of α and β ...<|control11|><|separator|>
[37]
The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression
In situations where the ∆p collapses, such as hypoxia/anoxia, the ATP synthase acts in reverse to maintain the ∆p at the expense of hydrolyzing ATP. The ATP ...
[38]
Structure, mechanism, and regulation of the chloroplast ATP synthase
May 11, 2018 · Hahn et al. show that chloroplast ATP synthase contains a built-in inhibitor triggered by oxidizing conditions in the dark chloroplast.
[39]
The Role of Light–Dark Regulation of the Chloroplast ATP Synthase
The chloroplast ATP synthase catalyzes the light-driven synthesis of ATP and is activated in the light and inactivated in the dark by redox-modulation ...
[40]
The Roles of ATP Synthase and the Cytochrome b6/f Complexes in ...
The cyclic electron transport can generate a ΔpH and drives ATP synthesis by ATP synthase without concomitant generation of NADPH (Shikanai, 2007). ATP and ...
[41]
The thermodynamic H+/ATP ratios of the H+-ATPsynthases ... - PNAS
The most recent data give H+/ATP = 4 for the chloroplast enzyme (32–34), whereas H+/ATP = 3 was reported for the mitochondrial enzyme (reviewed in ref. 35). Few ...
[42]
The regulatory subunit ε in Escherichia coli FOF1-ATP synthase - PMC
In bacteria they are present in the plasma membrane, whereas in animals and plants they are found in the inner mitochondrial membrane and the thylakoid membrane ...
[43]
ATP synthase: Evolution, energetics, and membrane interactions
Rotor ring stoichiometry ranges from 8 c-ring subunits in mammalian mitochondria (Zhou et al., 2015; Watt et al., 2010) to 17 in the human pathogen Burkholderia ...
[44]
The genes for the eight subunits of the membrane bound ATP ...
The ATP synthase genes, designated atp 1, are located at 83.2 min in a segment of the chromosome between 3.5 and 11.3 kb left (counterclockwise) of the origin ...Missing: plasma | Show results with:plasma
[45]
Structures of rotary ATP synthase from Thermus thermophilus during ...
Oct 17, 2025 · The majority of ATP in animal cells and prokaryotes is synthesized through phosphorylation of adenosine diphosphate (ADP) during respiration.
[46]
ATP synthases from archaea: the beauty of a molecular motor
Mar 17, 2014 · A1AO ATP synthases have distinct structural features such as a collar-like structure, an extended central stalk, and two peripheral stalks ...
[47]
Three-dimensional Structure of A1A0 ATP Synthase from the ...
Apr 10, 2009 · The archaeal ATP synthase is a multisubunit complex that consists of a catalytic A1 part and a transmembrane, ion translocation domain A0.
[48]
Adaptations of anaerobic archaea to life under extreme energy ...
A major functional difference is that the predominant physiological function of A1AO and F1FO ATP synthases is to synthesize ATP at the expense of an ...
[49]
Mitochondrial protein translocation machinery: From TOM structural ...
The TOM complex is the sole ATP-independent import machinery for nearly all of the ∼1000 to 1500 known mitochondrial proteins.Missing: IF1 IF2
[50]
Regulation of the H+-ATP synthase by IF1: a role in mitohormesis
Feb 6, 2017 · In humans, IF1 is encoded in the nuclear ATPIF1 gene, located in chromosome 1, is translated as a precursor protein that upon mitochondrial ...
[51]
Assembling the mitochondrial ATP synthase - PNAS
ATP6, together with the c-ring, forms the proton-conducting channel of the Fo region. The central c-ring is composed of eight or 10 identical subunits in human ...
[52]
Intertwined translational regulations set uneven stoichiometry of ...
CF1 subunits α, β and ɛ are expressed from the chloroplast genes atpA, atpB and atpE, respectively, while subunits γ and δ are expressed from the nuclear genes ...Missing: plastid | Show results with:plastid
[53]
Structural basis of redox modulation on chloroplast ATP synthase
Sep 2, 2020 · In higher plants, chloroplast ATP synthase has a unique redox switch on its γ subunit that modulates enzyme activity to limit ATP hydrolysis at night.<|control11|><|separator|>
[54]
Structure of the yeast F1Fo-ATP synthase dimer and its role ... - PNAS
Aug 3, 2012 · In mitochondria, the ATP synthase dimer has been shown to play a major role in shaping the cristae (40). On the basis of our computer ...
[55]
Structure of a mitochondrial ATP synthase with bound native ... - eLife
Nov 18, 2019 · It features 29 different subunits, 8 of which are newly identified. The membrane region was determined to 2.8 Å resolution, enabling the ...<|control11|><|separator|>
[56]
In situ structure of trypanosomal ATP synthase dimer reveals ... - PNAS
We determined the in situ structures of ATP synthase dimers from the lethal human parasite Trypanosoma brucei and its free-living relative Euglena gracilis.<|control11|><|separator|>
[57]
Rotor subunits adaptations in ATP synthases from photosynthetic ...
Apr 23, 2021 · In the plant ATP synthase, the c-ring stoichiometry is c14 [48], while in cyanobacteria the stoichiometry varies between 13 and 15 [49].
[58]
Optimization of ATP Synthase c–Rings for Oxygenic Photosynthesis
The apparent high H+/ATP ratio in chloroplasts (n=4.67) decreases the pmf required to overcome ΔGATP, allowing photosynthesis to produce ATP at a lower relative ...
[59]
F-Type ATP Synthase Assembly Factors Atp11 and Atp12 in ...
Oct 18, 2020 · Taken together, we conclude that while Atp12 is specifically targeted to the mitochondria, Atp11 is localized both in chloroplasts and ...
[60]
Approaches to defining dual‐targeted proteins in Arabidopsis
Mar 10, 2009 · Within a plant cell, mitochondria and chloroplasts have many enzymatic steps in common. Both contain ATP synthase complexes with similar ...<|control11|><|separator|>
[61]
ATP synthase from Trypanosoma brucei has an elaborated ... - PNAS
Feb 12, 2018 · The role of the peripheral stalk in ATP synthases is to provide the stator of the enzyme with integrity by connecting the α3β3-domain to the ...
[62]
architectural and functional oddities of the trypanosomal ATP synthase
For example, under ischaemic conditions in mammalian tissues, respiration is halted and the ATP synthase reverses in response to decreased mitochondrial ...
[63]
Engineering of ATP synthase for enhancement of proton-to-ATP ratio
Jul 3, 2025 · In this study, we seek to significantly enhance the H + /ATP ratio by employing an alternative approach that differs from that of nature.Missing: efficiency | Show results with:efficiency
[64]
ATP synthase evolution on a cross-braced dated tree of life - Nature
Nov 17, 2023 · Our analyses confirm the split of the catalytic and non-catalytic ATP synthase subunits prior to LUCA and reveal the prevalence and early ...<|control11|><|separator|>
[65]
Electron transport chains as a window into the earliest stages of ...
Aug 14, 2023 · Phylogenetic evidence strongly suggests that the ATP synthase complex predated the LUCA because the catalytic and noncatalytic subunits of ATP ...Electron Transport Chains As... · Abstract · Sign Up For Pnas Alerts
[66]
ATP synthase: two motors, two fuels - ScienceDirect
Apr 15, 1999 · ATP synthase: two motors, two fuels. Author links open overlay ... The largest portion of Fo comprises 12 c subunits, each consisting ...
[67]
ATP synthase evolution on a cross-braced dated tree of life - PMC
Our analyses confirm the split of the catalytic and non-catalytic ATP synthase subunits prior to LUCA and reveal the prevalence and early evolution of A/V-type ...
[68]
On the origin of biochemistry at an alkaline hydrothermal vent - PMC
A model for the origin of biochemistry at an alkaline hydrothermal vent has been developed that focuses on the acetyl-CoA (Wood–Ljungdahl) pathway of CO2 ...
[69]
https://pmc.ncbi.nlm.nih.gov/articles/PMC10656485/
[70]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2442388/
[71]
https://doi.org/10.1073/pnas.1303333110
[72]
An overview of ATP synthase, inhibitors, and their toxicity - PMC
Nov 20, 2023 · The drug has a novel mechanism of action that targets subunit c, thus blocking bacterial ATP synthases and preventing ATP synthesis [23].
[73]
ATPase Inhibitor Protein, IF 1 , by pH - ScienceDirect.com
The binding of IF1 to ATP synthase is dependent on pH. Upon reduction of pH below neutrality, the inhibitory capacity of IF1 increases (5). In respiring ...
[74]
Inhibitors of ATP Synthase as New Antibacterial Candidates - PMC
Mar 24, 2023 · Curcumin, a dietary phyto-polyphenol derived from the perennial herb curcuma longa, inhibits F1-ATP synthase activity by interfering with ...3. Therapeutical... · 3.1. 3. Bedaquiline · 3.2. 1. Oligomycin A
[75]
NARP syndrome in a patient harbouring an insertion in the MT-ATP6 ...
Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome have been associated to m.8993T>G/C mutations in the subunit 6 of the ATP synthase.
[76]
Delineating MT-ATP6-associated disease | Neurology Genetics
Jan 13, 2020 · 8993 T > G variant in 1992, more than 500 cases of ATP6-associated disease have been reported. The initially described phenotype is today ...
[77]
Entry - *516060 - ATP SYNTHASE 6; MTATP6 - OMIM - (OMIM.ORG)
Their results suggested that the 8993T-G mutation induces a structural defect in F1F0-ATPase that causes a severe impairment of ATP synthesis. Kerrison et al. ( ...
[78]
The ATP Synthase Deficiency in Human Diseases - MDPI
The first mutation was reported in the ATP5F1E gene, which encodes ε subunit in the central stalk of the enzyme [49]. More recently, different mutations were ...
[79]
FUS interacts with ATP synthase beta subunit and induces ... - PNAS
Sep 24, 2018 · Our data suggest that mitochondrial impairment may be a common pathogenic mechanism underlying FTLD-FUS and ALS-FUS, and that blocking ...
[80]
ATP synthase and Alzheimer's disease: putting a spin on the ...
Aug 31, 2020 · This review presents the evidence accumulated so far that demonstrates dysfunction of ATP synthase in AD, before highlighting two potential pharmacological ...
[81]
Mitochondrial ATP synthase activity is impaired by suppressed O ...
These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and ...
[82]
(PDF) ATP synthase and Alzheimer's disease: Putting a spin on the ...
Aug 6, 2025 · Similarly, Aβ-injected rats were reported to have decreased ATP synthase β-subunit levels, and gene expression analysis of AD patients' brains ...<|separator|>
[83]
ATP Synthase Abundance in Neuronal Extracellular Vesicles ...
Aug 6, 2025 · Furthermore, the NEV mitochondrial protein cargoes are aberrant in individuals with Alzheimer's disease (Yao et al. 2021), Parkinson's disease ( ...
[84]
Defueling the cancer: ATP synthase as an emerging target in cancer ...
Inhibiting the activity of ATP synthase can effectively impair tumor metabolism reprogramming and tumor growth. ATP synthase is essential for tumor progression ...
[85]
ATP synthase as an emerging target in cancer therapy - Cell Press
We review recent various ATP syn- thase inhibitors that suppress tumor growth and are being tested for the clinic. INTRODUCTION. A century ago, Warburg reported ...