Editing Oxidative phosphorylation (section)

== ATP synthase (complex V) ==
{{further|ATP synthase}}

ATP synthase, also called ''complex V'', is the final enzyme in the oxidative phosphorylation pathway. This enzyme is found in all forms of life and functions in the same way in both prokaryotes and eukaryotes.<ref name=Boyer>{{cite journal | vauthors = Boyer PD | title = The ATP synthase--a splendid molecular machine | journal = Annual Review of Biochemistry | volume = 66 | pages = 717–749 | year = 1997 | pmid = 9242922 | doi = 10.1146/annurev.biochem.66.1.717 }}</ref> The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and [[phosphate]] (P<sub>i</sub>). Estimates of the number of protons required to synthesize one ATP have ranged from three to four,<ref>{{cite journal | vauthors = Van Walraven HS, Strotmann H, Schwarz O, Rumberg B | title = The H+/ATP coupling ratio of the ATP synthase from thiol-modulated chloroplasts and two cyanobacterial strains is four | journal = FEBS Letters | volume = 379 | issue = 3 | pages = 309–313 | date = February 1996 | pmid = 8603713 | doi = 10.1016/0014-5793(95)01536-1 | bibcode = 1996FEBSL.379..309V | s2cid = 35989618 }}</ref><ref>{{cite journal | vauthors = Yoshida M, Muneyuki E, Hisabori T | title = ATP synthase--a marvellous rotary engine of the cell | journal = Nature Reviews. Molecular Cell Biology | volume = 2 | issue = 9 | pages = 669–677 | date = September 2001 | pmid = 11533724 | doi = 10.1038/35089509 | s2cid = 3926411 }}</ref> with some suggesting cells can vary this ratio, to suit different conditions.<ref>{{cite journal | vauthors = Schemidt RA, Qu J, Williams JR, Brusilow WS | title = Effects of carbon source on expression of F0 genes and on the stoichiometry of the c subunit in the F1F0 ATPase of Escherichia coli | journal = Journal of Bacteriology | volume = 180 | issue = 12 | pages = 3205–3208 | date = June 1998 | pmid = 9620972 | pmc = 107823 | doi = 10.1128/jb.180.12.3205-3208.1998 }}</ref>

{{NumBlk|:|<chem>ADP + P_i + 4H+_{intermembrane} <=> ATP + H2O + 4H+_{matrix}</chem>|{{EquationRef|6}}}}

This [[phosphorylation]] reaction is an [[chemical equilibrium|equilibrium]], which can be shifted by altering the proton-motive force. In the absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their concentration gradient and turning ADP into ATP.<ref name=Boyer/> Indeed, in the closely related [[V-ATPase|vacuolar type H+-ATPases]], the hydrolysis reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP.<ref>{{cite journal | vauthors = Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H | title = The cellular biology of proton-motive force generation by V-ATPases | journal = The Journal of Experimental Biology | volume = 203 | issue = Pt 1 | pages = 89–95 | date = January 2000 | pmid = 10600677 | doi = 10.1242/jeb.203.1.89 | bibcode = 2000JExpB.203...89N | url = http://jeb.biologists.org/cgi/reprint/203/1/89 | url-status = live | archive-url = https://web.archive.org/web/20070930043711/http://jeb.biologists.org/cgi/reprint/203/1/89 | archive-date = 30 September 2007 }}</ref>

ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains 16 subunits and has a mass of approximately 600 [[kilodalton]]s.<ref>{{cite journal | vauthors = Rubinstein JL, Walker JE, Henderson R | title = Structure of the mitochondrial ATP synthase by electron cryomicroscopy | journal = The EMBO Journal | volume = 22 | issue = 23 | pages = 6182–6192 | date = December 2003 | pmid = 14633978 | pmc = 291849 | doi = 10.1093/emboj/cdg608 }}</ref> The portion embedded within the membrane is called F<sub>O</sub> and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F<sub>1</sub> and is the site of ATP synthesis. The ball-shaped complex at the end of the F<sub>1</sub> portion contains six proteins of two different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with the tip of the stalk extending into the ball of α and β subunits.<ref>{{cite journal | vauthors = Leslie AG, Walker JE | title = Structural model of F1-ATPase and the implications for rotary catalysis | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 355 | issue = 1396 | pages = 465–471 | date = April 2000 | pmid = 10836500 | pmc = 1692760 | doi = 10.1098/rstb.2000.0588 }}</ref> Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F<sub>1</sub> portion and back into the membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme.

As protons cross the membrane through the channel in the base of ATP synthase, the F<sub>O</sub> proton-driven motor rotates.<ref>{{cite journal | vauthors = Noji H, Yoshida M | title = The rotary machine in the cell, ATP synthase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 3 | pages = 1665–1668 | date = January 2001 | pmid = 11080505 | doi = 10.1074/jbc.R000021200 | s2cid = 30953216 | doi-access = free }}</ref> Rotation might be caused by changes in the [[ionization]] of amino acids in the ring of c subunits causing [[electrostatic]] interactions that propel the ring of c subunits past the proton channel.<ref>{{cite journal | vauthors = Capaldi RA, Aggeler R | title = Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor | journal = Trends in Biochemical Sciences | volume = 27 | issue = 3 | pages = 154–160 | date = March 2002 | pmid = 11893513 | doi = 10.1016/S0968-0004(01)02051-5 }}<!--PubMed listing does use incorrect "F0" notation--></ref> This rotating ring in turn drives the rotation of the central [[axle]] (the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented from rotating themselves by the side-arm, which acts as a [[stator]]. This movement of the tip of the γ subunit within the ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements that produces and then releases ATP.<ref name=Dimroth2006>{{cite journal | vauthors = Dimroth P, von Ballmoos C, Meier T | title = Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series | journal = EMBO Reports | volume = 7 | issue = 3 | pages = 276–282 | date = March 2006 | pmid = 16607397 | pmc = 1456893 | doi = 10.1038/sj.embor.7400646 }}</ref>
[[File:ATPsyn.gif|thumb|220px|right|Mechanism of [[ATP synthase]]. ATP is shown in red, ADP and phosphate in pink and the rotating γ subunit in black.]]
This ATP synthesis reaction is called the ''binding change mechanism'' and involves the active site of a β subunit cycling between three states.<ref name=Gresser>{{cite journal | vauthors = Gresser MJ, Myers JA, Boyer PD | title = Catalytic site cooperativity of beef heart mitochondrial F1 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 | url = http://www.jbc.org/cgi/reprint/257/20/12030 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20070929103100/http://www.jbc.org/cgi/reprint/257/20/12030 | archive-date = 29 September 2007 }}</ref> In the "open" state, ADP and phosphate enter the active site (shown in brown in the diagram). The protein then closes up around the molecules and binds them loosely&nbsp;– the "loose" state (shown in red). The enzyme then changes shape again and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly produced ATP molecule with very high [[Dissociation constant|affinity]]. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle.

In some bacteria and archaea, ATP synthesis is driven by the movement of sodium ions through the cell membrane, rather than the movement of protons.<ref>{{cite journal | vauthors = Dimroth P | title = Bacterial sodium ion-coupled energetics | journal = Antonie van Leeuwenhoek | volume = 65 | issue = 4 | pages = 381–395 | year = 1994 | pmid = 7832594 | doi = 10.1007/BF00872221 | s2cid = 23763996 }}</ref><ref name=Becher>{{cite journal | vauthors = Becher B, Müller V | title = Delta mu Na+ drives the synthesis of ATP via an delta mu Na(+)-translocating F1F0-ATP synthase in membrane vesicles of the archaeon Methanosarcina mazei Gö1 | journal = Journal of Bacteriology | volume = 176 | issue = 9 | pages = 2543–2550 | date = May 1994 | pmid = 8169202 | pmc = 205391 | doi = 10.1128/jb.176.9.2543-2550.1994 }}</ref> Archaea such as ''[[Methanococcus]]'' also contain the A<sub>1</sub>A<sub>o</sub> synthase, a form of the enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP synthase subunits. It is possible that, in some species, the A<sub>1</sub>A<sub>o</sub> form of the enzyme is a specialized sodium-driven ATP synthase,<ref>{{cite journal | vauthors = Müller V | title = An exceptional variability in the motor of archael A1A0 ATPases: from multimeric to monomeric rotors comprising 6-13 ion binding sites | journal = Journal of Bioenergetics and Biomembranes | volume = 36 | issue = 1 | pages = 115–125 | date = February 2004 | pmid = 15168615 | doi = 10.1023/B:JOBB.0000019603.68282.04 | s2cid = 24887884 }}</ref> but this might not be true in all cases.<ref name=Becher/>