Editing ATP synthase

{{short description|Enzyme}}
{{Infobox enzyme
| Name = ATP Synthase
| EC_number = 7.1.2.2
| CAS_number= 9000-83-3
| GO_code = 0046961
| image = Atp synthase.PNG
| width = 250
| caption = Molecular model of ATP synthase determined by [[X-ray crystallography]]. Stator is not shown here.
}}

'''ATP synthase''' is an [[enzyme]] that catalyzes the formation of the energy storage molecule [[adenosine triphosphate]] (ATP) using [[adenosine diphosphate]] (ADP) and inorganic [[phosphate]] (P<sub>i</sub>). ATP synthase is a [[molecular machine]]. The overall reaction catalyzed by ATP synthase is:
* ADP + P<sub>i</sub> + 2H<sup>+</sup><sub>out</sub> {{Eqm}} ATP + H<sub>2</sub>O + 2H<sup>+</sup><sub>in</sub>

ATP synthase lies across a cellular membrane and forms an aperture that [[hydron (chemistry)|protons]] can cross from areas of high concentration to areas of low concentration, imparting energy for the synthesis of ATP. This [[electrochemical gradient]] is generated by the [[electron transport chain]] and allows cells to store energy in ATP for later use. In  [[prokaryote|prokaryotic cells]] ATP synthase lies across the [[plasma membrane]], while in  [[eukaryote|eukaryotic cells]] it lies across the [[inner mitochondrial membrane]]. Organisms capable of [[photosynthesis]] also have ATP synthase across the [[thylakoid membrane]], which in [[plants]] is located in the [[chloroplast]] and in [[cyanobacteria]] is located in the [[cytoplasm]].

Eukaryotic ATP synthases are [[F-ATPase]]s (which usually work as ATP synthases instead of ATPases in cellular environments) and running "in reverse" for an [[ATPase]] (ATPase [[Catalysis|catalyze]] the [[decomposition]] of [[Adenosine triphosphate|ATP]] into [[Adenosine diphosphate|ADP]] and a free [[Phosphate|phosphate ion]]). This article deals mainly with this type. An F-ATPase consists of two main subunits, F<sub>O</sub> and F<sub>1</sub>, which has a rotational motor mechanism allowing for ATP production.<ref name="Okuno_2011">{{cite journal | vauthors = Okuno D, Iino R, Noji H | title = Rotation and structure of FoF1-ATP synthase | journal = Journal of Biochemistry | volume = 149 | issue = 6 | pages = 655–664 | date = June 2011 | pmid = 21524994 | doi = 10.1093/jb/mvr049 | doi-access = free }}</ref><ref name="Junge_2015">{{cite journal | vauthors = Junge W, Nelson N | title = ATP synthase | journal = Annual Review of Biochemistry | volume = 84 | pages = 631–657 | date = June 2015 | pmid = 25839341 | doi = 10.1146/annurev-biochem-060614-034124 | doi-access = free }}</ref>

== Nomenclature ==
The F<sub>1</sub> fraction derives its name from the term "Fraction 1" and F<sub>O</sub> (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for [[oligomycin]], a type of naturally derived antibiotic that is able to inhibit the F<sub>O</sub> unit of ATP synthase.<ref name="Kagawa_1966">{{cite journal | vauthors = Kagawa Y, Racker E | title = Partial resolution of the enzymes catalyzing oxidative phosphorylation. 8. Properties of a factor conferring oligomycin sensitivity on mitochondrial adenosine triphosphatase | journal = The Journal of Biological Chemistry | volume = 241 | issue = 10 | pages = 2461–2466 | date = May 1966 | pmid = 4223640 | doi = 10.1016/S0021-9258(18)96640-8 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mccarty RE | title = A PLANT BIOCHEMIST'S VIEW OF H+-ATPases AND ATP SYNTHASES | journal = The Journal of Experimental Biology | volume = 172 | issue = Pt 1 | pages = 431–441 | date = November 1992 | pmid = 9874753 | doi = 10.1242/jeb.172.1.431 }}</ref> 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 ==
[[File:Fo subunit of ATPase C1. Picture Created in PyMol.png|thumb|289x289px|Bovine mitochondrial ATP synthase. The F<sub>O</sub>, F<sub>1</sub>, axle, and stator regions are color coded magenta, green, orange, and cyan respectively i.e. <span style="color:#f0f">F<sub>O</sub></span>, <span style="color:#0f0">F<sub>1</sub></span>, <span style="color:#f80">axle</span>, <span style="color:#0ff">stator</span>.<ref name="pmid26439008">{{PDB|5ARA}}; {{cite journal | vauthors = Zhou A, Rohou A, Schep DG, Bason JV, Montgomery MG, Walker JE, Grigorieff N, Rubinstein JL | display-authors = 6 | title = Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM | journal = eLife | volume = 4 | pages = e10180 | date = October 2015 | pmid = 26439008 | pmc = 4718723 | doi = 10.7554/eLife.10180 | doi-access = free }}</ref><ref>{{cite journal | doi = 10.2210/rcsb_pdb/mom_2005_12 | journal = Molecule of the Month | title = ATP Synthase | url = https://pdb101.rcsb.org/motm/72 | first = David | last = Goodsell | name-list-style = vanc | date = December 2005 | url-access = subscription }}</ref>]]
[[File:Atpsynthase.jpg|thumb|150px|Simplified model of F<sub>O</sub>F<sub>1</sub>-ATPase alias ATP synthase of ''E. coli''. Subunits of the enzyme are labeled accordingly.]]
[[File:Atpsyntase4.jpg|thumb|150px|Rotation engine of ATP synthase.]]

Located within the [[thylakoid membrane]] and the [[inner mitochondrial membrane]], ATP synthase consists of two regions F<sub>O</sub> and F<sub>1</sub>. F<sub>O</sub> causes rotation of F<sub>1</sub> and is made of c-ring and subunits a, two b, F6. F<sub>1</sub> is made of α, β, γ, and δ subunits. F<sub>1</sub> has a water-soluble part that can hydrolyze ATP. F<sub>O</sub> on the other hand has mainly hydrophobic regions. F<sub>O</sub> F<sub>1</sub> creates a pathway for protons movement across the membrane.<ref name="Velours_2000">{{cite journal | vauthors = Velours J, Paumard P, Soubannier V, Spannagel C, Vaillier J, Arselin G, Graves PV | title = Organisation of the yeast ATP synthase F(0):a study based on cysteine mutants, thiol modification and cross-linking reagents | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1458 | issue = 2–3 | pages = 443–456 | date = May 2000 | pmid = 10838057 | doi = 10.1016/S0005-2728(00)00093-1 | doi-access = free }}</ref>

=== F<sub>1</sub> region ===
The F<sub>1</sub> portion of ATP synthase is [[hydrophilic]] and responsible for hydrolyzing ATP. The F<sub>1</sub> unit protrudes into the [[mitochondrial matrix]] 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 F<sub>1</sub> 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 F<sub>1</sub> particle is large and can be seen in the transmission electron microscope by negative staining.<ref>{{cite journal | vauthors = Fernandez Moran H, Oda T, Blair PV, Green DE | title = A macromolecular repeating unit of mitochondrial structure and function. Correlated electron microscopic and biochemical studies of isolated mitochondria and submitochondrial particles of beef heart muscle | journal = The Journal of Cell Biology | volume = 22 | issue = 1 | pages = 63–100 | date = July 1964 | pmid = 14195622 | pmc = 2106494 | doi = 10.1083/jcb.22.1.63 }}</ref> These are particles of 9&nbsp;nm diameter that pepper the inner mitochondrial membrane.

{| class="wikitable" style="text-align:center"
|+ F<sub>1</sub> – Subunits<ref name=pmid24878343/>

|-
! Subunit !! Human Gene !! Note
|-
| [[ATP synthase alpha/beta subunits|alpha]] || ''[[ATP5A1]]'', ''[[ATPAF2]]'' ||
|-
| [[ATP synthase alpha/beta subunits|beta]] || ''[[ATP5B]]'', ''[[ATPAF1]]'' ||
|-
| [[ATP synthase gamma subunit|gamma]] || ''[[ATP5C1]]'' ||
|-
| [[ATP synthase delta/epsilon subunit|delta]] || ''[[ATP5D]]'' || Mitochondrial "delta" is bacterial/chloroplastic epsilon.
|-
| [[ATP synthase epsilon subunit, mitochondrial|epsilon]] || ''[[ATP5E]]'' || Unique to mitochondria.
|-
| [[ATP synthase delta/OSCP subunit|OSCP]] || ''[[ATP5O]]'' || Called "delta" in bacterial and chloroplastic versions.
|}

=== F<sub>O</sub> region ===
[[File:Fo complex subunit F6.png|thumb|285x285px|F<sub>O</sub> subunit F6 from the peripheral stalk region of ATP synthase.<ref name="Carbajo_2004">{{PDB|1VZS}}; {{cite journal | vauthors = Carbajo RJ, Silvester JA, Runswick MJ, Walker JE, Neuhaus D | title = Solution structure of subunit F(6) from the peripheral stalk region of ATP synthase from bovine heart mitochondria | journal = Journal of Molecular Biology | volume = 342 | issue = 2 | pages = 593–603 | date = September 2004 | pmid = 15327958 | doi = 10.1016/j.jmb.2004.07.013 }}</ref>]]

F<sub>O</sub> is a water [[insoluble]] protein with eight subunits and a transmembrane ring. The ring has a [[tetramer]]ic 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 F<sub>O</sub> which then also affects conformation of F<sub>1</sub>, resulting in switching of states of alpha and beta subunits. The F<sub>O</sub> 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 F<sub>1</sub> OSCP that prevents the αβ hexamer from rotating. Subunit a connects b to the c ring.<ref name=ecoli/> Humans have six additional subunits, [[ATP5H|d]], [[ATP5I|e]], [[ATP5J2|f]], [[ATP5L|g]], [[ATP5J|F6]], and [[MT-ATP8|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 F<sub>1</sub> region.

In eukaryotes, mitochondrial F<sub>O</sub> forms membrane-bending dimers. These dimers self-arrange into long rows at the end of the [[cristae]], possibly the first step of cristae formation.<ref>{{cite journal | vauthors = Blum TB, Hahn A, Meier T, Davies KM, Kühlbrandt W | title = Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 10 | pages = 4250–4255 | date = March 2019 | pmid = 30760595 | pmc = 6410833 | doi = 10.1073/pnas.1816556116 | bibcode = 2019PNAS..116.4250B | doi-access = free }}</ref> An atomic model for the dimeric yeast F<sub>O</sub> region was determined by cryo-EM at an overall resolution of 3.6 Å.<ref>{{cite journal | vauthors = Guo H, Bueler SA, Rubinstein JL | title = Atomic model for the dimeric F<sub>O</sub> region of mitochondrial ATP synthase | journal = Science | volume = 358 | issue = 6365 | pages = 936–940 | date = November 2017 | pmid = 29074581 | pmc = 6402782 | doi = 10.1126/science.aao4815 | bibcode = 2017Sci...358..936G }}</ref>
{| class="wikitable" style="text-align:center"
|+ F<sub>O</sub>-Main subunits
|-
! Subunit !! Human Gene
|-
| a || ''[[MT-ATP6]]''
|-
| b || ''[[ATP5PB]]''
|-
| [[ATP synthase subunit C|c]] || ''[[ATP5MC1]]'', ''[[ATP5G2]]'', ''[[ATP5G3]]''
|-
|}

== Binding model ==
[[File:ATPsyn.gif|thumb|220px|right|Mechanism of ATP synthase. ADP and P<sub>i</sub> (pink) shown being combined into ATP (red), while the rotating γ (gamma) subunit in black causes conformational change.]]
[[File:ATP-Synthase.svg|thumb|230px|Depiction of ATP synthase using the [[Chemiosmosis|chemiosmotic]] proton gradient to power ATP synthesis through [[oxidative phosphorylation]].]]
In the 1960s through the 1970s, [[Paul D. Boyer|Paul Boyer]], a [[University of California, Los Angeles|UCLA]] 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 [[Laboratory of Molecular Biology|MRC Laboratory of Molecular Biology]] in [[Cambridge]], crystallized the F<sub>1</sub> 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]].

The crystal structure of the F<sub>1</sub> showed alternating alpha and beta [[Protein subunit|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 F<sub>O</sub> region of ATP synthase. A portion of the F<sub>O</sub> (the ring of [[ATP synthase subunit C|c-subunits]]) [[Rotating locomotion in living systems|rotates]] as the protons pass through the membrane. The [[ATP synthase subunit C|c-ring]] is tightly attached to the asymmetric central stalk (consisting primarily of the gamma subunit), causing it to rotate within the alpha<sub>3</sub>beta<sub>3</sub> of F<sub>1</sub> causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that lead to ATP synthesis. The major F<sub>1</sub> subunits are prevented from rotating in sympathy with the central stalk rotor by a peripheral stalk that joins the alpha<sub>3</sub>beta<sub>3</sub> to the non-rotating portion of F<sub>O</sub>. 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 F<sub>1</sub> to F<sub>O</sub>. Under the right conditions, the enzyme reaction can also be carried out in reverse, with ATP hydrolysis driving [[proton pump]]ing across the membrane.

The binding change mechanism involves the active site of a β subunit's cycling between three states.<ref name=Gresser>{{cite journal | vauthors = Gresser MJ, Myers JA, Boyer PD | title = Catalytic site cooperativity of beef heart mitochondrial F<sub>1</sub> adenosine triphosphatase. Correlations of initial velocity, bound intermediate, and oxygen exchange measurements with an alternating three-site model | journal = The Journal of Biological Chemistry | volume = 257 | issue = 20 | pages = 12030–12038 | date = October 1982 | pmid = 6214554 | doi = 10.1016/S0021-9258(18)33672-X | doi-access = free }}</ref> 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 [[Dissociation constant|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.<ref name=Nakamoto>{{cite journal | vauthors = Nakamoto RK, Baylis Scanlon JA, Al-Shawi MK | title = The rotary mechanism of the ATP synthase | journal = Archives of Biochemistry and Biophysics | volume = 476 | issue = 1 | pages = 43–50 | date = August 2008 | pmid = 18515057 | pmc = 2581510 | doi = 10.1016/j.abb.2008.05.004 }}</ref>

== Physiological role ==

Like other enzymes, the activity of F<sub>1</sub>F<sub>O</sub> ATP synthase is reversible. Large-enough quantities of ATP cause it to create a transmembrane [[proton]] [[gradient]], 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]] and the transport of nutrients into the cell.

In respiring [[bacteria]] under physiological conditions, ATP synthase, in general, runs in the opposite direction, creating ATP while using the [[electrochemical potential|proton motive force]] created by the [[electron transfer chain|electron transport chain]] as a source of energy. The overall process of creating energy in this fashion is termed [[oxidative phosphorylation]].
The same process takes place in the [[mitochondria]], where ATP synthase is located in the inner mitochondrial membrane and the F<sub>1</sub>-part projects into the [[mitochondrial matrix]]. By pumping proton cations into the matrix, the ATP-synthase converts ADP into ATP.

== Evolution ==
The [[evolution]] of ATP synthase is thought to have been modular whereby two functionally independent subunits became associated and gained new functionality.<ref name=RotaryDNA>{{cite journal | vauthors = Doering C, Ermentrout B, Oster G | title = Rotary DNA motors | journal = Biophysical Journal | volume = 69 | issue = 6 | pages = 2256–2267 | date = December 1995 | pmid = 8599633 | pmc = 1236464 | doi = 10.1016/S0006-3495(95)80096-2 | bibcode = 1995BpJ....69.2256D }}</ref><ref name=LifeScience_IL>{{cite web |first=Antony |last=Crofts |name-list-style=vanc |url=http://www.life.illinois.edu/crofts/bioph354/lect10.html |title=Lecture 10:ATP synthase |publisher=Life Sciences at the [[University of Illinois at Urbana–Champaign]]}}</ref> 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.<ref name=RotaryDNA /> The F-ATP synthase displays high functional and mechanistic similarity to the [[V-ATPase]].<ref name=InterPro_Synthase>{{cite web |url=http://www.ebi.ac.uk/interpro/potm/2005_12/Page2.htm |work=InterPro Database |title=ATP Synthase }}</ref> 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.<ref>{{cite journal | vauthors = Beyenbach KW, Wieczorek H | title = The V-type H+ ATPase: molecular structure and function, physiological roles and regulation | journal = The Journal of Experimental Biology | volume = 209 | issue = Pt 4 | pages = 577–589 | date = February 2006 | pmid = 16449553 | doi = 10.1242/jeb.02014 | doi-access = free }}</ref>

<!-- FIXME: Since F1 is now linked to T3SS ring too, this needs a rewrite! -->
The F<sub>1</sub> region also shows significant similarity to hexameric [[DNA helicase]]s (especially the [[Rho factor]]), and the entire enzyme region shows some similarity to {{chem|H|+}}-powered [[T3SS]] or [[Flagellum#Motor|flagellar motor]] complexes.<ref name=InterPro_Synthase /><ref>{{cite journal | vauthors = Skordalakes E, Berger JM | title = Structure of the Rho transcription terminator: mechanism of mRNA recognition and helicase loading | journal = Cell | volume = 114 | issue = 1 | pages = 135–146 | date = July 2003 | pmid = 12859904 | doi = 10.1016/S0092-8674(03)00512-9 | s2cid = 5765103 | doi-access = free }}</ref><ref name=T3SS>{{cite journal | vauthors = Imada K, Minamino T, Uchida Y, Kinoshita M, Namba K | title = Insight into the flagella type III export revealed by the complex structure of the type III ATPase and its regulator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 13 | pages = 3633–3638 | date = March 2016 | pmid = 26984495 | pmc = 4822572 | doi = 10.1073/pnas.1524025113 | doi-access = free | bibcode = 2016PNAS..113.3633I }}</ref> The α<sub>3</sub>β<sub>3</sub> hexamer of the F<sub>1</sub> 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 α<sub>3</sub>β<sub>3</sub> hexamer uses the conformational changes through the rotation of the γ subunit to drive an enzymatic reaction.<ref name=EctopicATP>{{cite journal | vauthors = Martinez LO, Jacquet S, Esteve JP, Rolland C, Cabezón E, Champagne E, Pineau T, Georgeaud V, Walker JE, Tercé F, Collet X, Perret B, Barbaras R | display-authors = 6 | title = Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis | journal = Nature | volume = 421 | issue = 6918 | pages = 75–79 | date = January 2003 | pmid = 12511957 | doi = 10.1038/nature01250 | s2cid = 4333137 | bibcode = 2003Natur.421...75M }}</ref>

The {{chem|H|+}} motor of the F<sub>O</sub> particle shows great functional similarity to the {{chem|H|+}} motors that drive flagella.<ref name=InterPro_Synthase /> Both feature a ring of many small alpha-helical proteins that rotate relative to nearby stationary proteins, using a {{chem|H|+}} 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 F<sub>O</sub> particle and the ring with about 30 rotating proteins is far larger than the 10, 11, or 14 helical proteins in the F<sub>O</sub> complex. More recent structural data do however show that the ring and the stalk are structurally similar to the F<sub>1</sub> particle.<ref name=T3SS/>

[[File:ATP synthesis - ATP synthase rotation.ogv|thumb|right|230px|Conformation changes of ATP synthase during synthesis]]
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 {{chem|H|+}} motor, were able to bind, and the rotation of the motor drove the ATPase activity of the helicase in reverse.<ref name=RotaryDNA /><ref name=EctopicATP /> This complex then evolved greater efficiency and eventually developed into today's intricate ATP synthases. Alternatively, the DNA helicase/{{chem|H|+}} motor complex may have had {{chem|H|+}} pump activity with the ATPase activity of the helicase driving the {{chem|H|+}} motor in reverse.<ref name=RotaryDNA /> This may have evolved to carry out the reverse reaction and act as an ATP synthase.<ref name=LifeScience_IL /><ref name=Cross1990>{{cite journal | vauthors = Cross RL, Taiz L | title = Gene duplication as a means for altering H+/ATP ratios during the evolution of F<sub>O</sub>F<sub>1</sub> ATPases and synthases | journal = FEBS Letters | volume = 259 | issue = 2 | pages = 227–229 | date = January 1990 | pmid = 2136729 | doi = 10.1016/0014-5793(90)80014-a | s2cid = 32559858 | doi-access = free }}</ref><ref name=Cross2004>{{cite journal | vauthors = Cross RL, Müller V | title = The evolution of A-, F-, and V-type ATP synthases and ATPases: reversals in function and changes in the H+/ATP coupling ratio | journal = FEBS Letters | volume = 576 | issue = 1–2 | pages = 1–4 | date = October 2004 | pmid = 15473999 | doi = 10.1016/j.febslet.2004.08.065 | s2cid = 25800744 | doi-access = free }}</ref>

==Inhibitors==
A variety of natural and synthetic inhibitors of ATP synthase have been discovered.<ref name="inhibitors">{{cite journal | vauthors = Hong S, Pedersen PL | title = ATP synthase and the actions of inhibitors utilized to study its roles in human health, disease, and other scientific areas | journal = Microbiology and Molecular Biology Reviews | volume = 72 | issue = 4 | pages = 590–641, Table of Contents | date = December 2008 | pmid = 19052322 | pmc = 2593570 | doi = 10.1128/MMBR.00016-08 }}</ref> 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.<ref name="inhibitors"/> Some of the most commonly used ATP synthase inhibitors are [[oligomycin]] and [[N,N'-Dicyclohexylcarbodiimide|DCCD]].

== In different organisms ==
=== Bacteria ===
''{{vanchor|E. coli}}'' ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types.<ref name=ecoli>{{cite journal | vauthors = Ahmad Z, Okafor F, Laughlin TF | title = Role of Charged Residues in the Catalytic Sites of Escherichia coli ATP Synthase | journal = Journal of Amino Acids | volume = 2011 | pages = 785741 | year = 2011 | pmid = 22312470 | pmc = 3268026 | doi = 10.4061/2011/785741 | doi-access = free }}</ref>

Bacterial F-ATPases can occasionally operate in reverse, turning them into an ATPase.<ref name=pmid26671611>{{cite journal | vauthors = Kühlbrandt W, Davies KM | title = Rotary ATPases: A New Twist to an Ancient Machine | journal = Trends in Biochemical Sciences | volume = 41 | issue = 1 | pages = 106–116 | date = January 2016 | pmid = 26671611 | doi = 10.1016/j.tibs.2015.10.006 }}</ref> Some bacteria have no F-ATPase, using an A/V-type ATPase bidirectionally.<ref name=pmid24878343/>

=== Yeast ===
Yeast ATP synthase is one of the best-studied eukaryotic ATP synthases; and five F<sub>1</sub>, eight F<sub>O</sub> subunits, and seven associated proteins have been identified.<ref name="Velours_2000" /> Most of these proteins have homologues in other eukaryotes.<ref>{{cite journal | vauthors = Devenish RJ, Prescott M, Roucou X, Nagley P | title = Insights into ATP synthase assembly and function through the molecular genetic manipulation of subunits of the yeast mitochondrial enzyme complex | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1458 | issue = 2–3 | pages = 428–442 | date = May 2000 | pmid = 10838056 | doi = 10.1016/S0005-2728(00)00092-X | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kabaleeswaran V, Puri N, Walker JE, Leslie AG, Mueller DM | title = Novel features of the rotary catalytic mechanism revealed in the structure of yeast F<sub>1</sub> ATPase | journal = The EMBO Journal | volume = 25 | issue = 22 | pages = 5433–5442 | date = November 2006 | pmid = 17082766 | pmc = 1636620 | doi = 10.1038/sj.emboj.7601410 }}</ref><ref>{{cite journal | vauthors = Stock D, Leslie AG, Walker JE | title = Molecular architecture of the rotary motor in ATP synthase | journal = Science | volume = 286 | issue = 5445 | pages = 1700–1705 | date = November 1999 | pmid = 10576729 | doi = 10.1126/science.286.5445.1700 }}</ref><ref>{{cite journal | vauthors = Liu S, Charlesworth TJ, Bason JV, Montgomery MG, Harbour ME, Fearnley IM, Walker JE | title = The purification and characterization of ATP synthase complexes from the mitochondria of four fungal species | journal = The Biochemical Journal | volume = 468 | issue = 1 | pages = 167–175 | date = May 2015 | pmid = 25759169 | pmc = 4422255 | doi = 10.1042/BJ20150197 }}</ref>

=== Plant ===
In plants, ATP synthase is also present in [[chloroplasts]] (CF<sub>1</sub>F<sub>O</sub>-ATP synthase). The enzyme is integrated into [[thylakoid]] membrane; the CF<sub>1</sub>-part sticks into [[stroma (fluid)|stroma]], where dark reactions of photosynthesis (also called the light-independent reactions or the [[Calvin cycle]]) 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 [[electrochemical potential|proton motive force]] 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.<ref>{{cite journal | vauthors = Hahn A, Vonck J, Mills DJ, Meier T, Kühlbrandt W | title = Structure, mechanism, and regulation of the chloroplast ATP synthase | journal = Science | volume = 360 | issue = 6389 | pages = eaat4318 | date = May 2018 | pmid = 29748256 | pmc = 7116070 | doi = 10.1126/science.aat4318 | doi-access = free }}</ref>

=== Mammal ===
{{anchor|Bovine}}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.<ref>{{cite journal | vauthors = Abrahams JP, Leslie AG, Lutter R, Walker JE | title = Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria | journal = Nature | volume = 370 | issue = 6491 | pages = 621–628 | date = August 1994 | pmid = 8065448 | doi = 10.1038/370621a0 | s2cid = 4275221 | bibcode = 1994Natur.370..621A }}</ref><ref>{{cite journal | vauthors = Gibbons C, Montgomery MG, Leslie AG, Walker JE | title = The structure of the central stalk in bovine F(1)-ATPase at 2.4 A resolution | journal = Nature Structural Biology | volume = 7 | issue = 11 | pages = 1055–1061 | date = November 2000 | pmid = 11062563 | doi = 10.1038/80981 | s2cid = 23229994 }}</ref><ref>{{cite journal | vauthors = Menz RI, Walker JE, Leslie AG | title = Structure of bovine mitochondrial F(1)-ATPase with nucleotide bound to all three catalytic sites: implications for the mechanism of rotary catalysis | journal = Cell | volume = 106 | issue = 3 | pages = 331–341 | date = August 2001 | pmid = 11509182 | doi = 10.1016/s0092-8674(01)00452-4 | s2cid = 1266814 | doi-access = free }}</ref>

{{anchor|Human}}Human genes that encode components of ATP synthases:
* ''[[ATP synthase, H+ transporting, mitochondrial F1 complex, alpha 1|ATP5A1]]''
* ''[[ATP5B]]''
* ''[[ATP5C1]]'', ''[[ATP5D]]'', ''[[ATP5E]]'', ''[[ATP5F1]]'', ''[[ATP5MC1]]'', ''[[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 F<sub>1</sub> head like other mitochondrial ATP synthases, but the F<sub>O</sub> subcomplex has many unique subunits. It uses [[cardiolipin]]. The inhibitory IF<sub>1</sub> also binds differently, in a way shared with [[trypanosomatida]].<ref>{{cite journal | vauthors = Mühleip A, McComas SE, Amunts A | title = Structure of a mitochondrial ATP synthase with bound native cardiolipin | journal = eLife | volume = 8 | pages = e51179 | date = November 2019 | pmid = 31738165 | pmc = 6930080 | doi = 10.7554/eLife.51179 | doi-access = free }}
* {{cite web |date=December 24, 2019 |title=Different from the rest |website=eLife |url=https://elifesciences.org/digests/51179/different-from-the-rest}}</ref>

=== 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.<ref name=pmid26671611/> Like the bacteria F-ATPase, it is believed to also function as an ATPase.<ref name=pmid24878343>{{cite journal | vauthors = Stewart AG, Laming EM, Sobti M, Stock D | title = Rotary ATPases--dynamic molecular machines | journal = Current Opinion in Structural Biology | volume = 25 | pages = 40–48 | date = April 2014 | pmid = 24878343 | doi = 10.1016/j.sbi.2013.11.013 | doi-access = free }}</ref>

=== 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 LUCA.<ref>{{cite journal | vauthors = Matzke NJ, Lin A, Stone M, Baker MA | title = Flagellar export apparatus and ATP synthetase: Homology evidenced by synteny predating the Last Universal Common Ancestor | journal = BioEssays | volume = 43 | issue = 7 | pages = e2100004 | date = July 2021 | pmid = 33998015 | doi = 10.1002/bies.202100004 | s2cid = 234747849 | hdl = 2292/55176 | hdl-access = free }}</ref>

== See also ==
{{div col|colwidth=25em}}
* [[ATP10 protein]] required for the assembly of the F<sub>O</sub> sector of the mitochondrial ATPase complex.
* [[Chloroplast]]
* [[Electron transfer chain]]
* [[Flavoprotein]]
* [[Mitochondrion]]
* [[Oxidative phosphorylation]]
* [[P-ATPase]]
* [[Proton pump]]
* [[Rotating locomotion in living systems]]
* [[Transmembrane ATPase]]
* [[V-ATPase]]
{{Div col end}}

== References ==
{{Reflist|33em}}

== Further reading ==
* Nick Lane: [https://books.google.com/books?id=IfJYBQAAQBAJ&dq=nick+lane+the+vital+question+f0+f1+atp+synthase&pg=PT77 ''The Vital Question: Energy, Evolution, and the Origins of Complex Life''], Ww Norton, 2015-07-20, {{ISBN|978-0393088816}} (Link points to Figure 10 showing model of ATP synthase)

== External links ==
* Boris A. Feniouk: [http://www.atpsynthase.info/ "ATP synthase — a splendid molecular machine"]
* Well illustrated [http://www.life.uiuc.edu/crofts/bioph354/lect10.html ATP synthase lecture] by Antony Crofts of the [[University of Illinois at Urbana–Champaign]].
* [http://opm.phar.umich.edu/families.php?superfamily=5 Proton and Sodium translocating F-type, V-type and A-type ATPases in OPM database]
* [http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/illpres/index.html The Nobel Prize in Chemistry 1997] 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, {{chem|Na|+}}, {{chem|K|+}}-ATPase.
* [https://web.archive.org/web/20080422024412/http://multimedia.mcb.harvard.edu/media.html Harvard Multimedia Production Site — Videos] – ATP synthesis animation
* David Goodsell: [http://www.rcsb.org/pdb/101/motm.do?momID=72 "ATP Synthase- Molecule of the Month"] {{Webarchive|url=https://web.archive.org/web/20150905064626/http://www.rcsb.org/pdb/101/motm.do?momID=72 |date=2015-09-05 }}

{{ATPase}}
{{Mitochondrial DNA}}
{{Acid anhydride hydrolases}}
{{Enzymes}}
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[[Category:Enzymes]]
[[Category:Cellular respiration]]
[[Category:Photosynthesis]]
[[Category:EC 3.6.3]]
[[Category:Integral membrane proteins]]
[[Category:Protein complexes]]