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ATP synthase is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
that catalyzes the formation of the energy storage molecule
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all ...
(ATP) using
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells (biology), cells. ADP consists of three important structural components: ...
(ADP) and inorganic
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...
(Pi). It is classified under ligases as it changes ADP by the formation of P-O bond (phosphodiester bond). ATP synthase is a
molecular machine A molecular machine, nanite, or nanomachine is a molecular component that produces quasi-mechanical movements (output) in response to specific stimuli (input). In cellular biology, macromolecular machines frequently perform tasks essential for l ...
. The overall reaction catalyzed by ATP synthase is: * ADP + Pi + 2H+out ATP + H2O + 2H+in The formation of ATP from ADP and Pi is energetically unfavorable and would normally proceed in the reverse direction. In order to drive this reaction forward, ATP synthase couples ATP synthesis during
cellular respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
to an
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in Concentration, solute concentration across a me ...
created by the difference in
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
(H+) concentration across the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. Th ...
in
eukaryotes Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
or the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the cytoplasm, interior of all Cell (biology), cells from th ...
in bacteria. During
photosynthesis Photosynthesis is a process used by plants and other organisms to Energy transformation, convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemica ...
in plants, ATP is synthesized by ATP synthase using a proton gradient created in the thylakoid lumen through the thylakoid membrane and into the chloroplast stroma. Eukaryotic ATP synthases are F-ATPases, running "in reverse" for an ATPase. This article deals mainly with this type. An F-ATPase consists of two main subunits, FO and F1, which has a rotational motor mechanism allowing for ATP production.


Nomenclature

The F1 fraction derives its name from the term "Fraction 1" and FO (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for
oligomycin Oligomycins are macrolides created by ''Streptomyces'' that can be poisonous to other organisms. Function They have use as antibiotics. Oligomycin A is an inhibitor of ATP synthase. In oxidative phosphorylation research, it is used to prevent ...
, a type of naturally derived antibiotic that is able to inhibit the FO unit of ATP synthase. These functional regions consist of different protein subunits — refer to tables. This enzyme is used in synthesis of ATP through aerobic respiration.


Structure and function

Located within the
thylakoid membrane Thylakoids are membrane-bound compartments inside chloroplasts and cyanobacterium, cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. Thylakoids consist of a thylakoid membrane surrounding a thylakoid lumen (an ...
and the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. Th ...
, ATP synthase consists of two regions FO and F1. FO causes rotation of F1 and is made of c-ring and subunits a, two b, F6. F1 is made of α, β, γ, and δ subunits. F1 has a water-soluble part that can hydrolyze ATP. FO on the other hand has mainly hydrophobic regions. FO F1 creates a pathway for protons movement across the membrane.


F1 region

The F1 portion of ATP synthase is
hydrophilic A hydrophile is a molecule or other molecular entity that is intermolecular force, attracted to water molecules and tends to be dissolution (chemistry), dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clar ...
and responsible for hydrolyzing ATP. The F1 unit protrudes into the
mitochondrial matrix In the mitochondrion, the matrix is the space within the Inner mitochondrial membrane, inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contain ...
space. Subunits α and β make a hexamer with 6 binding sites. Three of them are catalytically inactive and they bind ADP. Three other subunits catalyze the ATP synthesis. The other F1 subunits γ, δ, and ε are a part of a rotational motor mechanism (rotor/axle). The γ subunit allows β to go through conformational changes (i.e., closed, half open, and open states) that allow for ATP to be bound and released once synthesized. The F1 particle is large and can be seen in the transmission electron microscope by negative staining. These are particles of 9 nm diameter that pepper the inner mitochondrial membrane.


FO region

FO is a water
insoluble In chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, st ...
protein with eight subunits and a transmembrane ring. The ring has a tetramer shape with a helix loop helix protein that goes through conformational changes when protonated and deprotonated, pushing neighboring subunits to rotate, causing the spinning of FO which then also affects conformation of F1, resulting in switching of states of alpha and beta subunits. The FO region of ATP synthase is a proton pore that is embedded in the mitochondrial membrane. It consists of three main subunits, a, b, and c. Six c subunits make up the rotor ring, and subunit b makes up a stalk connecting to F1 OSCP that prevents the αβ hexamer from rotating. Subunit a connects b to the c ring. Humans have six additional subunits, d, e, f, g, F6, and 8 (or A6L). This part of the enzyme is located in the mitochondrial inner membrane and couples proton translocation to the rotation that causes ATP synthesis in the F1 region. In eukaryotes, mitochondrial FO forms membrane-bending dimers. These dimers self-arrange into long rows at the end of the cristae, possibly the first step of cristae formation. An atomic model for the dimeric yeast FO region was determined by cryo-EM at an overall resolution of 3.6 Å.


Binding model

In the 1960s through the 1970s, Paul Boyer, a
UCLA The University of California, Los Angeles (UCLA) is a public university, public Land-grant university, land-grant research university in Los Angeles, California. UCLA's academic roots were established in 1881 as a Normal school, teachers colle ...
Professor, developed the binding change, or flip-flop, mechanism theory, which postulated that ATP synthesis is dependent on a conformational change in ATP synthase generated by rotation of the gamma subunit. The research group of John E. Walker, then at the MRC Laboratory of Molecular Biology in
Cambridge Cambridge ( ) is a College town, university city and the county town in Cambridgeshire, England. It is located on the River Cam approximately north of London. As of the 2021 United Kingdom census, the population of Cambridge was 145,700. Cam ...
, crystallized the F1 catalytic-domain of ATP synthase. The structure, at the time the largest asymmetric protein structure known, indicated that Boyer's rotary-catalysis model was, in essence, correct. For elucidating this, Boyer and Walker shared half of the 1997
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
. The crystal structure of the F1 showed alternating alpha and beta subunits (3 of each), arranged like segments of an orange around a rotating asymmetrical gamma subunit. According to the current model of ATP synthesis (known as the alternating catalytic model), the transmembrane potential created by (H+) proton cations supplied by the electron transport chain, drives the (H+) proton cations from the intermembrane space through the membrane via the FO region of ATP synthase. A portion of the FO (the ring of c-subunits) rotates as the protons pass through the membrane. The c-ring is tightly attached to the asymmetric central stalk (consisting primarily of the gamma subunit), causing it to rotate within the alpha3beta3 of F1 causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that lead to ATP synthesis. The major F1 subunits are prevented from rotating in sympathy with the central stalk rotor by a peripheral stalk that joins the alpha3beta3 to the non-rotating portion of FO. The structure of the intact ATP synthase is currently known at low-resolution from electron cryo-microscopy (cryo-EM) studies of the complex. The cryo-EM model of ATP synthase suggests that the peripheral stalk is a flexible structure that wraps around the complex as it joins F1 to FO. Under the right conditions, the enzyme reaction can also be carried out in reverse, with ATP hydrolysis driving proton pumping across the membrane. The binding change mechanism involves the active site of a β subunit's cycling between three states. In the "loose" state, ADP and phosphate enter the active site; in the adjacent diagram, this is shown in pink. The enzyme then undergoes a change in shape and forces these molecules together, with the active site in the resulting "tight" state (shown in red) binding the newly produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state (orange), releasing ATP and binding more ADP and phosphate, ready for the next cycle of ATP production.


Physiological role

Like other enzymes, the activity of F1FO ATP synthase is reversible. Large-enough quantities of ATP cause it to create a transmembrane
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
gradient In vector calculus, the gradient of a scalar-valued function, scalar-valued differentiable function of Function of several variables, several variables is the vector field (or vector-valued function) \nabla f whose value at a point p is the "d ...
, this is used by fermenting bacteria that do not have an electron transport chain, but rather hydrolyze ATP to make a proton gradient, which they use to drive
flagella A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide Motility#Cellular level, motility. Many protists with flagella are termed as flagellates. A m ...
and the transport of nutrients into the cell. In respiring
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometre The micrometre (Amer ...
under physiological conditions, ATP synthase, in general, runs in the opposite direction, creating ATP while using the
proton motive force Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ion ...
created by the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that electron transfer, transfer electrons from electron donors to electron acceptors via redox reactions (both Redox#Definitions, reduction and oxidation occu ...
as a source of energy. The overall process of creating energy in this fashion is termed
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order t ...
. The same process takes place in the
mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which i ...
, where ATP synthase is located in the inner mitochondrial membrane and the F1-part projects into the
mitochondrial matrix In the mitochondrion, the matrix is the space within the Inner mitochondrial membrane, inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contain ...
. By pumping proton cations into the matrix, the ATP-synthase converts ADP into ATP.


Evolution

The
evolution Evolution is change in the heredity, heritable Phenotypic trait, characteristics of biological populations over successive generations. These characteristics are the Gene expression, expressions of genes, which are passed on from parent to ...
of ATP synthase is thought to have been modular whereby two functionally independent subunits became associated and gained new functionality. This association appears to have occurred early in evolutionary history, because essentially the same structure and activity of ATP synthase enzymes are present in all kingdoms of life. The F-ATP synthase displays high functional and mechanistic similarity to the V-ATPase. However, whereas the F-ATP synthase generates ATP by utilising a proton gradient, the V-ATPase generates a proton gradient at the expense of ATP, generating pH values of as low as 1. The F1 region also shows significant similarity to hexameric
DNA helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's DNA, genetic material. Helicases are motor proteins that move Directionality (molecular biology), directionally along a nucleic a ...
s (especially the Rho factor), and the entire enzyme region shows some similarity to -powered T3SS or flagellar motor complexes. The α3β3 hexamer of the F1 region shows significant structural similarity to hexameric DNA helicases; both form a ring with 3-fold rotational symmetry with a central pore. Both have roles dependent on the relative rotation of a macromolecule within the pore; the DNA helicases use the helical shape of DNA to drive their motion along the DNA molecule and to detect supercoiling, whereas the α3β3 hexamer uses the conformational changes through the rotation of the γ subunit to drive an enzymatic reaction. The motor of the FO particle shows great functional similarity to the motors that drive flagella. Both feature a ring of many small alpha-helical proteins that rotate relative to nearby stationary proteins, using a potential gradient as an energy source. This link is tenuous, however, as the overall structure of flagellar motors is far more complex than that of the FO particle and the ring with about 30 rotating proteins is far larger than the 10, 11, or 14 helical proteins in the FO complex. More recent structural data do however show that the ring and the stalk are structurally similar to the F1 particle. The modular evolution theory for the origin of ATP synthase suggests that two subunits with independent function, a DNA helicase with ATPase activity and a motor, were able to bind, and the rotation of the motor drove the ATPase activity of the helicase in reverse. This complex then evolved greater efficiency and eventually developed into today's intricate ATP synthases. Alternatively, the DNA helicase/ motor complex may have had pump activity with the ATPase activity of the helicase driving the motor in reverse. This may have evolved to carry out the reverse reaction and act as an ATP synthase.


Inhibitors

A variety of natural and synthetic inhibitors of ATP synthase have been discovered. These have been used to probe the structure and mechanism of ATP synthase. Some may be of therapeutic use. There are several classes of ATP synthase inhibitors, including peptide inhibitors, polyphenolic phytochemicals, polyketides, organotin compounds, polyenic α-pyrone derivatives, cationic inhibitors, substrate analogs, amino acid modifiers, and other miscellaneous chemicals. Some of the most commonly used ATP synthase inhibitors are
oligomycin Oligomycins are macrolides created by ''Streptomyces'' that can be poisonous to other organisms. Function They have use as antibiotics. Oligomycin A is an inhibitor of ATP synthase. In oxidative phosphorylation research, it is used to prevent ...
and DCCD.


In different organisms


Bacteria

' ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types. Bacterial F-ATPases can occasionally operate in reverse, turning them into an ATPase. Some bacteria have no F-ATPase, using an A/V-type ATPase bidirectionally.


Yeast

Yeast ATP synthase is one of the best-studied eukaryotic ATP synthases; and five F1, eight FO subunits, and seven associated proteins have been identified. Most of these proteins have homologues in other eukaryotes.


Plant

In plants, ATP synthase is also present in
chloroplasts A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, ...
(CF1FO-ATP synthase). The enzyme is integrated into
thylakoid Thylakoids are membrane-bound compartments inside chloroplasts and cyanobacterium, cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. Thylakoids consist of a thylakoid membrane surrounding a thylakoid lumen (an ...
membrane; the CF1-part sticks into stroma, where dark reactions of photosynthesis (also called the light-independent reactions or the
Calvin cycle The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
) and ATP synthesis take place. The overall structure and the catalytic mechanism of the chloroplast ATP synthase are almost the same as those of the bacterial enzyme. However, in chloroplasts, the
proton motive force Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ion ...
is generated not by respiratory electron transport chain but by primary photosynthetic proteins. The synthase has a 40-aa insert in the gamma-subunit to inhibit wasteful activity when dark.


Mammal

The ATP synthase isolated from bovine (''Bos taurus'') heart mitochondria is, in terms of biochemistry and structure, the best-characterized ATP synthase. Beef heart is used as a source for the enzyme because of the high concentration of mitochondria in cardiac muscle. Their genes have close homology to human ATP synthases. Human genes that encode components of ATP synthases: *
ATP5A1 ATP synthase F1 subunit alpha, mitochondrial is an enzyme that in humans is encoded by the ''ATP5F1A'' gene. Function This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electr ...
*
ATP5B ATP synthase F1 subunit beta, mitochondrial is an enzyme that in humans is encoded by the ''ATP5F1B'' gene. Function This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an el ...
*
ATP5C1 The human ATP5F1C gene encodes the gamma subunit of an enzyme called mitochondrial ATP synthase. This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes adenosine triphosphate (ATP) synthesis, utilizing an ...
, ATP5D, ATP5E, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5I, ATP5J, ATP5J2, ATP5L, ATP5O * MT-ATP6, MT-ATP8


Other eukaryotes

Eukaryotes belonging to some divergent lineages have very special organizations of the ATP synthase. A euglenozoa ATP synthase forms a dimer with a boomerang-shaped F1 head like other mitochondrial ATP synthases, but the FO subcomplex has many unique subunits. It uses
cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...
. The inhibitory IF1 also binds differently, in a way shared with trypanosomatida.


Archaea

Archaea do not generally have an F-ATPase. Instead, they synthesize ATP using the A-ATPase/synthase, a rotary machine structurally similar to the V-ATPase but mainly functioning as an ATP synthase. Like the bacteria F-ATPase, it is believed to also function as an ATPase.


LUCA and earlier

F-ATPase gene linkage and gene order are widely conserved across ancient prokaryote lineages, implying that this system already existed at a date before the
last universal common ancestor The last universal common ancestor (LUCA) is the most recent population from which all organisms now living on Earth share common descent—the most recent common ancestor of all current life on Earth. This includes all cellular organisms; ...
, the LUCA.


See also

* ATP10 protein required for the assembly of the FO sector of the mitochondrial ATPase complex. *
Chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, ...
* Electron transfer chain *
Flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. Flavoproteins are involved in a wide array of biological processes, including removal of Radical (chemistry), radicals contributing to oxidative stress, photosynthes ...
*
Mitochondrion A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
*
Oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order t ...
* P-ATPase * Proton pump *
Rotating locomotion in living systems Rotation, or spin, is the circular movement of an object around a ''axis of rotation, central axis''. A two-dimensional rotating object has only one possible central axis and can rotate in either a clockwise or counterclockwise direction. A t ...
* Transmembrane ATPase * V-ATPase


References


Further reading

* Nick Lane
''The Vital Question: Energy, Evolution, and the Origins of Complex Life''
Ww Norton, 2015-07-20, (Link points to Figure 10 showing model of ATP synthase)


External links

* Boris A. Feniouk
"ATP synthase — a splendid molecular machine"
* Well illustrate

by Antony Crofts of the
University of Illinois at Urbana–Champaign The University of Illinois Urbana-Champaign (U of I, Illinois, University of Illinois, or UIUC) is a public university, public land-grant university, land-grant research university in Illinois in the twin cities of Champaign, Illinois, Champai ...
.
Proton and Sodium translocating F-type, V-type and A-type ATPases in OPM database


to Paul D. Boyer and John E. Walker for the enzymatic mechanism of synthesis of ATP; and to Jens C. Skou, for discovery of an ion-transporting enzyme, , -ATPase.

– ATP synthesis animation * David Goodsell
"ATP Synthase- Molecule of the Month"
{{Portal bar, Biology, border=no Enzymes Cellular respiration Photosynthesis EC 3.6.3 Integral membrane proteins Protein complexes