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| {{Infobox protein family
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| | Symbol = UCR_TM
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| | Name = UCR_TM
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| | image = Cytochrome1ntz.PNG
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| | width =
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| | caption = Crystal structure of mitochondrial cytochrome bc1 complex bound with [[ubiquinone]].<ref name="pmid12885240">{{PDB|1ntz}}; {{cite journal | author = Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA, Xia D | title = Structural basis for the quinone reduction in the bc1 complex: a comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site | journal = Biochemistry | volume = 42 | issue = 30 | pages = 9067–80 |date=August 2003 | pmid = 12885240 | doi = 10.1021/bi0341814 | url = }}</ref>
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| | Pfam = PF02921
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| | Pfam_clan =
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| | InterPro = IPR004192
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| | SMART =
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| | PROSITE =
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| | MEROPS =
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| | SCOP = 1be3
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| | TCDB = 3.D.3
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| | OPM family = 345
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| | OPM protein = 3cx5
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| | CAZy =
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| | CDD =
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| }}
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| {{enzyme
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| | Name = ubiquinol—cytochrome-c reductase
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| | EC_number = 1.10.2.2
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| | CAS_number = 9027-03-6
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| | IUBMB_EC_number = 1/10/2/2
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| | GO_code = 0008121
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| | image =
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| | width =
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| | caption =
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| }}
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| [[Image:Complex III.png|thumb|250px|schematic illustration of complex III reactions]]
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| The '''coenzyme Q : cytochrome ''c'' — oxidoreductase''', sometimes called the '''cytochrome ''bc''<sub>1</sub> complex''', and at other times '''complex III''', is the third complex in the [[electron transport chain]] ({{EC number|1.10.2.2}}), playing a critical role in biochemical generation of ATP ([[oxidative phosphorylation]]). Complex III is a multisubunit transmembrane protein encoded by both the mitochondrial ([[cytochrome b]]) and the nuclear genomes (all other subunits). Complex III is present in the [[mitochondria]] of all animals and all aerobic eukaryotes and the inner membranes of most [[eubacteria]]. Mutations in Complex III cause [[exercise intolerance]] as well as multisystem disorders. The bc1 [[complex (chemistry)|complex]] contains 11 subunits, 3 respiratory [[protein subunit|subunits]] (cytochrome B, [[cytochrome]] C1, Rieske protein), 2 core [[protein]]s and 6 low-molecular [[body weight|weight]] [[protein]]s.
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| Ubiquinol—cytochrome-c reductase catalyzes the chemical reaction
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| :QH<sub>2</sub> + 2 ferricytochrome c <math>\rightleftharpoons</math> Q + 2 ferrocytochrome c + 2 H<sup>+</sup>
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| Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are dihydroquinone (QH2) and ferri- (Fe<sup>3+</sup>) [[cytochrome c]], whereas its 3 [[product (chemistry)|products]] are [[quinone]] (Q), ferro- (Fe<sup>2+</sup>) cytochrome c, and [[hydrogen ion|H<sup>+</sup>]].
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| This enzyme belongs to the family of [[oxidoreductase]]s, specifically those acting on diphenols and related substances as donor with a cytochrome as acceptor. This enzyme participates in [[oxidative phosphorylation]]. It has four [[cofactor (biochemistry)|cofactors]]: [[cytochrome C1]], [[cytochrome b-562]], [[cytochrome b-566]] and a 2-Iron [[ferredoxin]].
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| == Nomenclature ==
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| The systematic name of this enzyme class is '''ubiquinol:ferricytochrome-c oxidoreductase'''. Other names in common use include:
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| {|
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| * coenzyme Q-cytochrome c reductase,
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| * dihydrocoenzyme Q-cytochrome c reductase,
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| * reduced ubiquinone-cytochrome c reductase, complex III,
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| * (mitochondrial electron transport),
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| * ubiquinone-cytochrome c reductase,
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| * ubiquinol-cytochrome c oxidoreductase,
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| * reduced coenzyme Q-cytochrome c reductase,
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| * ubiquinone-cytochrome c oxidoreductase,
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| * reduced ubiquinone-cytochrome c oxidoreductase,
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| * mitochondrial electron transport complex III,
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| * ubiquinol-cytochrome c-2 oxidoreductase,
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| * ubiquinone-cytochrome b-c1 oxidoreductase,
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| * ubiquinol-cytochrome c2 reductase,
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| * ubiquinol-cytochrome c1 oxidoreductase,
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| * CoQH2-cytochrome c oxidoreductase,
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| * ubihydroquinol:cytochrome c oxidoreductase,
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| * coenzyme QH2-cytochrome c reductase, and
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| * QH2:cytochrome c oxidoreductase.
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| |}
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| == Human gene names ==
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| [[MTCYB]]: [[mtDNA]] encoded cytochrome b; mutations associated with exercise intolerance
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| [[CYC1]]:cytochrome c1
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| [[Cytochrome c|CYCS]]: cytochrome c
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| [[UQCRFS1]]: Rieske iron sulfur protein
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| [[UQCRB]]: Ubiquinone binding protein, mutation linked with mitochondrial complex III deficiency nuclear type 3
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| [[UQCRH]]: hinge protein
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| [[UQCRC2]]: Core 2, mutations linked to mitochondrial complex III deficiency, nuclear type 5
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| [[UQCRC1]]: Core 1
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| [[UQCR]]: 6.4KD subunit
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| [[UQCR10]]: 7.2KD subunit
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| [[TTC19]]: Newly identified subunit, mutations linked to complex III deficiency nuclear type 2
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| == Structure ==
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| [[Image:Cytochrome bc1 complex.png|thumb|400px|Structure of complex III]]
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| Compared to the other major proton-pumping subunits of the [[Electron transfer chain|electron transport chain]], the number of subunits found can be small, as small as three polypeptide chains. This number does increase, and eleven subunits are found in higher animals.<ref name="pmid9651245">{{cite journal | author = Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK | title = Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex | journal = Science | volume = 281 | issue = 5373 | pages = 64–71 |date=July 1998 | pmid = 9651245 | doi =10.1126/science.281.5373.64 | url = | issn = }}</ref> Three subunits have [[prosthetic group]]s. The [[Cytochrome b|cytochrome ''b'' subunit]] has two ''b''-type [[heme]]s (''b''<sub>L</sub> and ''b''<sub>H</sub>), the cytochrome ''c'' subunit has one ''c''-type heme ([[Cytochrome C1|''c''<sub>1</sub>]]), and the Rieske Iron Sulfur Protein subunit (ISP) has a two iron, two sulfur [[iron-sulfur cluster]] (2Fe•2S).
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| Structures of complex III: {{PDB|1KYO}}, {{PDB|1L0L}}
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| ==Reaction==
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| It catalyzes the reduction of [[Cytochrome c|cytochrome ''c'']] by
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| oxidation of [[coenzyme Q]] (CoQ) and the concomitant pumping of 4 [[protons]] from the mitochondrial matrix to the intermembrane space:
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| : QH<sub>2</sub> + 2 cytochrome ''c'' (Fe<sup>III</sup>) + 2 H<sup>+</sup><sub>in</sub> → Q + 2 cytochrome ''c'' (Fe<sup>II</sup>) + 4 H<sup>+</sup><sub>out</sub>
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| In the process called [[Q cycle]],<ref name="pmid15047094">{{cite journal | author = Kramer DM, Roberts AG, Muller F, Cape J, Bowman MK | title = Q-cycle bypass reactions at the Qo site of the cytochrome bc1 (and related) complexes | journal = Meth. Enzymol. | volume = 382 | issue = | pages = 21–45 | year = 2004 | pmid = 15047094 | doi = 10.1016/S0076-6879(04)82002-0 | url = | issn = | series = Methods in Enzymology | isbn = 978-0-12-182786-1 }}</ref><ref name="pmid14977419">{{cite journal | author = Crofts AR | title = The cytochrome bc1 complex: function in the context of structure | journal = Annu. Rev. Physiol. | volume = 66 | issue = | pages = 689–733 | year = 2004 | pmid = 14977419 | doi = 10.1146/annurev.physiol.66.032102.150251 | url = | issn = }}</ref> two protons are consumed from the matrix (M), four protons are released into the inter membrane space (IM) and two electrons are passed to cytochrome ''c''.
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| ==Reaction mechanism==
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| [[Image:Theqcycle.gif|thumb|400px|The Q cycle]]
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| The reaction mechanism for complex III (cytochrome bc1, coenzyme Q: cytochrome C oxidoreductase) is known as the ubiquinone ("Q") cycle. In this cycle four protons get released into the positive "P" side (inter membrane space), but only two protons get taken up from the negative "N" side (matrix). As a result a [[proton gradient]] is formed across the membrane. In the overall reaction, two [[ubiquinol]]s are oxidized to [[ubiquinone]]s and one [[ubiquinone]] is reduced to [[ubiquinol]]. In the complete mechanism, two electrons are transferred from ubiquinol to ubiquinone, via two cytochrome c intermediates.
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| '''Overall''':
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| * 2 x QH<sub>2</sub> '''oxidised''' to Q
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| * 1 x Q '''reduced''' to QH<sub>2</sub>
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| * 2 x Cyt c<sub>1</sub> '''reduced'''
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| * 4 x H<big>+</big> released into intermembrane space
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| * 2 x H<sup>+</sup> picked up from matrix
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| The reaction proceeds according to the following steps:
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| '''Round 1''':
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| # Cytochrome b binds a ubiquinol and a ubiquinone.
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| # The 2Fe/2S center and B<sub>L</sub> heme each pull an electron off the bound ubiquinol, releasing two hydrogens into the intermembrane space.
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| # One electron is transferred to cytochrome c<sub>1</sub> from the 2Fe/2S centre, whilst another is transferred from the B<sub>L</sub> heme to the B<sub>H</sub> Heme.
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| # Cytochrome c<sub>1</sub> transfers its electron to [[cytochrome c]] (not to be confused with cytochrome c1), and the B<sub>H</sub> Heme transfers its electron to a nearby ubiquinone, resulting in the formation of a ubisemiquinone.
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| # Cytochrome c diffuses. The first ubiquinol (now oxidised to ubiquinone) is released, whilst the semiquinone remains bound.
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| '''Round 2''':
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| # A second ubiquinol is bound by cytochrome b.
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| # The 2Fe/2S center and B<sub>L</sub> heme each pull an electron off the bound ubiquinol, releasing two hydrogens into the intermembrane space.
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| # One electron is transferred to cytochrome c<sub>1</sub> from the 2Fe/2S centre, whilst another is transferred from the B<sub>L</sub> heme to the B<sub>H</sub> Heme.
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| # Cytocrome c<sub>1</sub> then transfers its electron to [[cytochrome c]], whilst the nearby semiquinone picks up a second electron from the B<sub>H</sub> heme, along with two protons from the matrix.
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| # The second ubiquinol (now oxidised to ubiquinone), along with the newly formed ubiquinol are released.<ref name="isbn0-12-518121-3">{{cite book | author = Ferguson SJ, Nicholls D, Ferguson S | authorlink = | editor = | others = | title = Bioenergetics | edition = 3rd | language = | publisher = Academic | location = San Diego | year = 2002 | origyear = | pages = 114–117 | quote = | isbn = 0-12-518121-3 | oclc = | doi = | url = | accessdate = }}</ref>
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| == Inhibitors of complex III ==
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| There are three distinct groups of Complex III inhibitors.
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| * [[antimycin|Antimycin A]] binds to the Q<sub>i</sub> site and inhibits the transfer of electrons in Complex III from heme ''b''<sub>H</sub> to oxidized Q (Qi site inhibitor).
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| * [[Myxothiazol]] and [[stigmatellin]] binds to the Q<sub>o</sub> site and inhibits the transfer of electrons from reduced QH<sub>2</sub> to the Rieske Iron sulfur protein. Myxothiazol and stigmatellin bind to distinct pockets within the Q<sub>o</sub> site.
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| ** Myxothiazol binds very close to cytochrome bL (hence termed a "proximal" inhibitor).
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| ** Stigmatellin binds near the Rieske Iron sulfur protein, with which it strongly interacts.
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| Some have been commercialized as fungicides (the [[strobilurin]] derivatives, best known of which is [[azoxystrobin]]; [[QoI]] inhibitors) and as anti-malaria agents ([[atovaquone]]).
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| Also [[propylhexedrine]] inhibits cytochrome c reductase.<ref name="pmid241101">http://www.ncbi.nlm.nih.gov/pubmed/241101</ref>
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| == Oxygen free radicals ==
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| A small fraction of electrons leave the electron transport chain before reaching [[complex IV]]. Premature electron leakage to [[oxygen]] results in the formation of [[superoxide]]. The relevance of this otherwise minor side reaction is that [[superoxide]] and other [[reactive oxygen species]] are highly toxic and are thought to play a role in several pathologies, as well as aging (the [[free radical theory of aging]]).<ref name="pmid17640558">{{cite journal | author = Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. | title = Trends in oxidative aging theories | journal = Free Radic. Biol. Med. | volume = 43 | issue = 4 | pages = 477–503 | year = 2007 | pmid = 17640558 | doi =10.1016/j.freeradbiomed.2007.03.034 | url = }}</ref> Electron leakage occurs mainly at the Q<sub>o</sub> site and is stimulated by [[antimycin A]]. [[Antimycin A]] locks the ''b'' hemes in the reduced state by preventing their re-oxidation at the Q<sub>i</sub> site, which, in turn, causes the steady-state concentrations of the Q<sub>o</sub> semiquinone to rise, the latter species reacting with [[oxygen]] to form [[superoxide]]. The effect of high membrane potential is thought to have a similar effect.<ref name="pmid8870073">{{cite journal | author = Skulachev VP | title = Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants | journal = Q. Rev. Biophys. | volume = 29 | issue = 2 | pages = 169–202 |date=May 1996 | pmid = 8870073 | doi = | url = | issn = }}</ref> [[Superoxide]] produced at the Qo site can be released both into the mitochondrial matrix<ref name="Muller, F. 2000">{{cite journal | author = Muller F | title = The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging | journal = AGE | year = 2000 | volume = 23 | issue = 4 | pages = 227–253 | doi = 10.1007/s11357-000-0022-9 }}</ref><ref name="Muller, F. L. 2004">{{cite journal | author = Muller FL, Liu Y, Van Remmen H | title = Complex III releases superoxide to both sides of the inner mitochondrial membrane | journal = J. Biol. Chem. | volume = 279 | issue = 47 | pages = 49064–73 |date=November 2004 | pmid = 15317809 | doi = 10.1074/jbc.M407715200 | url = | issn = }}</ref> and into the intermembrane space (from where it can reach the cytosol.<ref name="Muller, F. 2000"/><ref name="pmid11139407">{{cite journal | author = Han D, Williams E, Cadenas E | title = Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space | journal = Biochem. J. | volume = 353 | issue = Pt 2 | pages = 411–6 |date=January 2001 | pmid = 11139407 | pmc = 1221585 | doi = 10.1042/0264-6021:3530411| url = | issn = }}</ref> This could be explained by the fact that Complex III might produce [[superoxide]] as membrane permeable [[hydroperoxyl|HOO<sup>•</sup>]] rather than as membrane impermeable [[superoxide|O<sub>2</sub><sup>-.</sup>]].<ref name="Muller, F. L. 2004"/>
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| == Mutations in Complex III genes in human disease ==
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| Mutations in Complex III-related genes typically manifest as exercise intolerance.<ref name="pmid17053512">{{cite journal | author = DiMauro S | title = Mitochondrial myopathies | journal = Curr Opin Rheumatol | volume = 18 | issue = 6 | pages = 636–41 |date=November 2006 | pmid = 17053512 | doi = 10.1097/01.bor.0000245729.17759.f2 | url = | issn = }}</ref><ref name="pmid17484047">{{cite journal | author = DiMauro S | title = Mitochondrial DNA medicine | journal = Biosci. Rep. | volume = 27 | issue = 1–3 | pages = 5–9 |date=June 2007 | pmid = 17484047 | doi = 10.1007/s10540-007-9032-5 | url = | issn = }}</ref> Other mutations have been reported to cause septo-optic dysplasia<ref name="pmid11891837">{{cite journal | author = Schuelke M, Krude H, Finckh B, Mayatepek E, Janssen A, Schmelz M, Trefz F, Trijbels F, Smeitink J | title = Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation | journal = Ann. Neurol. | volume = 51 | issue = 3 | pages = 388–92 |date=March 2002 | pmid = 11891837 | doi = 10.1002/ana.10151| url = | issn = }}</ref> and multisystem disorders.<ref name="pmid11601507">{{cite journal | author = Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J | title = Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene | journal = Ann. Neurol. | volume = 50 | issue = 4 | pages = 540–3 |date=October 2001 | pmid = 11601507 | doi = 10.1002/ana.1224 | url = | issn = }}</ref> However, mutations in [[BCS1L]], a gene responsible for proper maturation of Complex III, can result in [[Björnstad syndrome]] and the [[GRACILE syndrome]], which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. The pathogenicity of several mutations has been verified in model systems such as yeast.<ref name="pmid14718526">{{cite journal | author = Fisher N, Castleden CK, Bourges I, Brasseur G, Dujardin G, Meunier B | title = Human disease-related mutations in cytochrome b studied in yeast | journal = J. Biol. Chem. | volume = 279 | issue = 13 | pages = 12951–8 |date=March 2004 | pmid = 14718526 | doi = 10.1074/jbc.M313866200 | url = | issn = }}</ref>
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| The extent to which these various pathologies are due to bioenergetic deficits or overproduction of [[superoxide]] is presently unknown.
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| == See also ==
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| *[[Cellular respiration]]
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| *[[Photosynthetic reaction centre]]
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| ==Additional images==
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| <gallery>
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| Image:Etc2.svg|ETC
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| </gallery>
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| == References ==
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| {{reflist|2}}
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| == Further reading ==
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| {{refbegin}}
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| * {{cite journal | doi = 10.1016/0005-2728(77)90099-8 | author = Marres CM, Slater EC | year = 1977 | title = Polypeptide composition of purified QH2:cytochrome c oxidoreductase from beef-heart mitochondria | journal = Biochim. Biophys. Acta. | volume = 462 | pages = 531–548 | pmid = 597492 | issue = 3 }}
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| * {{cite journal | author = Rieske JS | year = 1976 | title = Composition, structure, and function of complex III of the respiratory chain | journal = Biochim. Biophys. Acta. | volume = 456 | pages = 195–247 | pmid = 788795 | issue = 2 }}
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| * {{cite journal | author = Wikstrom M, Krab K, Saraste M | year = 1981 | title = Proton-translocating cytochrome complexes | journal = Annu. Rev. Biochem. | volume = 50 | pages = 623–655 | pmid = 6267990 | doi = 10.1146/annurev.bi.50.070181.003203 }}
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| {{refend}}
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| == External links ==
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| * [http://sb20.lbl.gov/cytbc1 cytochrome ''bc''<sub>1</sub> complex site (Edward A. Berry)] at lbl.gov
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| * [http://www.life.uiuc.edu/crofts/bc-complex_site cytochrome ''bc''<sub>1</sub> complex site (Antony R. Crofts)] at uiuc.edu
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| * [http://metallo.scripps.edu/PROMISE/CYTBC1.html PROMISE Database: cytochrome ''bc''<sub>1</sub> complex] at scripps.edu
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| * [http://www2.ufp.pt/~pedros/anim/2frame-iiien.htm Interactive Molecular Model of Complex III] (Requires [http://www.mdl.com/products/framework/chime/ MDL Chime])
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| * {{UMichOPM|families|superfamily|3}} - Calculated positions of bc1 and related complexes in membranes
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| * {{MeshName|Coenzyme+Q-Cytochrome-c+Reductase}}
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| {{Diphenol family oxidoreductases}}
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| {{Electron transport chain}}
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| {{Proton pumps}}
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| {{Mitochondrial DNA}}
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| {{DEFAULTSORT:Coenzyme Q - cytochrome c reductase}}
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| [[Category:EC 1.10.2]]
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| [[Category:Enzymes of known structure]]
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| [[Category:Cellular respiration]]
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| [[Category:Iron-sulfur proteins]]
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| [[Category:Integral membrane proteins]]
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