Coenzyme Q – cytochrome c reductase

The systematic name of this enzyme class is ubiquinol:ferricytochrome-c oxidoreductase. Other names in common use include:

File:Cytochrome bc1 complex.png

Compared to the other major proton-pumping subunits of the 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.{{cite journal | vauthors = 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 | bibcode = 1998Sci...281...64I }} Three subunits have prosthetic groups. The cytochrome b subunit has two b-type hemes (b_L and b_H), the cytochrome c subunit has one c-type heme (c₁), and the Rieske Iron Sulfur Protein subunit (ISP) has a two iron, two sulfur iron-sulfur cluster (2Fe•2S).

Structures of complex III: {{PDB|1KYO}}, {{PDB|1L0L}}

{{clear}}

In vertebrates the bc₁ complex, or Complex III, contains 11 subunits: 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.{{cite journal | vauthors=Zhang Z, Huang L, Shulmeister VM, Chi YI, Kim KK, Hung LW| title=Electron transfer by domain movement in cytochrome bc1. | journal=Nature | year= 1998 | volume= 392 | issue= 6677 | pages= 677–84 | doi=10.1038/33612 | pmid=9565029 | bibcode=1998Natur.392..677Z | s2cid=4380033 |display-authors=etal}}{{cite journal| vauthors=Hao GF, Wang F, Li H, Zhu XL, Yang WC, Huang LS| title=Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex. | journal=J Am Chem Soc | year= 2012 | volume= 134 | issue= 27 | pages= 11168–76 | doi=10.1021/ja3001908 | pmid=22690928 |display-authors=etal}} Proteobacterial complexes may contain as few as three subunits.{{cite journal |pmid=3017970 |vauthors=Yang XH, Trumpower BL |year=1986 |journal=J Biol Chem |volume=261 |issue=26 |pages=12282–9 |title=Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans|doi=10.1016/S0021-9258(18)67236-9 |doi-access=free }}

• ^a In vertebrates, a cleavage product of 8 kDa from the N-terminus of the Rieske protein (Signal peptide) is retained in the complex as subunit 9. Thus subunits 10 and 11 correspond to fungal QCR9p and QCR10p.

File:Complex III.png

It catalyzes the reduction of cytochrome c by

oxidation of coenzyme Q (CoQ) and the concomitant pumping of 4 protons from the mitochondrial matrix to the intermembrane space:

: QH₂ + 2 cytochrome c (Fe^III) + 2 H{{su|p=+|b=in}} → Q + 2 cytochrome c (Fe^II) + 4 H{{su|p=+|b=out}}

In the process called Q cycle,{{cite book|author1-link=David M. Kramer (biophysicist) | vauthors = Kramer DM, Roberts AG, Muller F, Cape J, Bowman MK | chapter = Q-Cycle Bypass Reactions at the Qo Site of the Cytochrome bc1 (And Related) Complexes | title = Quinones and Quinone Enzymes, Part B | volume = 382 | pages = 21–45 | year = 2004 | pmid = 15047094 | doi = 10.1016/S0076-6879(04)82002-0 | series = Methods in Enzymology | isbn = 978-0-12-182786-1 }}{{cite journal | author = Crofts AR | title = The cytochrome bc1 complex: function in the context of structure | journal = Annu. Rev. Physiol. | volume = 66 | pages = 689–733 | year = 2004 | pmid = 14977419 | doi = 10.1146/annurev.physiol.66.032102.150251 }} 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.

File:Theqcycle.gif

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 ubiquinols are oxidized to ubiquinones and one ubiquinone is reduced to ubiquinol. In the complete mechanism, two electrons are transferred from ubiquinol to ubiquinone, via two cytochrome c intermediates.

Overall:

• 2 x QH₂ oxidised to Q
• 1 x Q reduced to QH₂
• 2 x Cyt c reduced
• 4 x H⁺ released into intermembrane space
• 2 x H⁺ picked up from matrix

The reaction proceeds according to the following steps:

Round 1:

1. Cytochrome b binds a ubiquinol and a ubiquinone.
2. The 2Fe/2S center and B_L heme each pull an electron off the bound ubiquinol, releasing two protons into the intermembrane space.
3. One electron is transferred to cytochrome c₁ from the 2Fe/2S centre, whilst another is transferred from the B_L heme to the B_H Heme.
4. Cytochrome c₁ transfers its electron to cytochrome c (not to be confused with cytochrome c1), and the B_H Heme transfers its electron to a nearby ubiquinone, resulting in the formation of a ubisemiquinone.
5. Cytochrome c diffuses. The first ubiquinol (now oxidised to ubiquinone) is released, whilst the semiquinone remains bound.

Round 2:

1. A second ubiquinol is bound by cytochrome b.
2. The 2Fe/2S center and B_L heme each pull an electron off the bound ubiquinol, releasing two protons into the intermembrane space.
3. One electron is transferred to cytochrome c₁ from the 2Fe/2S centre, whilst another is transferred from the B_L heme to the B_H Heme.
4. Cytochrome c₁ then transfers its electron to cytochrome c, whilst the nearby semiquinone produced from round 1 picks up a second electron from the B_H heme, along with two protons from the matrix.
5. The second ubiquinol (now oxidised to ubiquinone), along with the newly formed ubiquinol are released.{{cite book | vauthors = Ferguson SJ, Nicholls D, Ferguson S | title = Bioenergetics | edition = 3rd | publisher = Academic | location = San Diego | year = 2002 | pages = 114–117 | isbn = 978-0-12-518121-1 }}

There are three distinct groups of Complex III inhibitors.

• Antimycin A binds to the Q_i site and inhibits the transfer of electrons in Complex III from heme b_H to oxidized Q (Qi site inhibitor).
• Myxothiazol and stigmatellin binds to the Q_o site and inhibits the transfer of electrons from reduced QH₂ to the Rieske Iron sulfur protein. Myxothiazol and stigmatellin bind to distinct but overlapping pockets within the Q_o site.
• Myxothiazol binds nearer to cytochrome bL (hence termed a "proximal" inhibitor).
• Stigmatellin binds farther from heme bL and nearer the Rieske Iron sulfur protein, with which it strongly interacts.

Some have been commercialized as fungicides (the strobilurin derivatives, best known of which is azoxystrobin; QoI inhibitors) and as anti-malaria agents (atovaquone). Some Q_o site inhibitors have been commercialized as insecticides (IRAC group 20).{{Cite book |last=Jeschke |first=Peter |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9783527699261 |title=Modern Crop Protection Compounds |last2=Witschel |first2=Matthias |last3=Krämer |first3=Wolfgang |last4=Schirmer |first4=Ulrich |date=25 January 2019 |publisher=Wiley‐VCH |isbn=9783527699261 |edition=3rd |pages=1156-1201 |chapter=32.3 Inhibitors of Mitochondrial Electron Transport: Acaricides and Insecticides}}

Also propylhexedrine inhibits cytochrome c reductase.{{Cite journal

| pmid = 241101

| year = 1975

| last1 = Holmes

| first1 = J. H.

| title = Inhibitory effect of anti-obesity drugs on NADH dehydrogenase of mouse heart homogenates

| journal = Research Communications in Chemical Pathology and Pharmacology

| volume = 11

| issue = 4

| pages = 645–6

| last2 = Sapeika

| first2 = N

| last3 = Zwarenstein

| first3 = H

}}

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).{{cite journal | author = Muller, F. L. | author2 = Lustgarten, M. S. | author3 = Jang, Y. | author4 = Richardson, A. | author5 = Van Remmen, H. | name-list-style = amp | 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 }} Electron leakage occurs mainly at the Q_o 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_i site, which, in turn, causes the steady-state concentrations of the Q_o 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.{{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 = 10.1017/s0033583500005795| s2cid = 40859585 }} Superoxide produced at the Qo site can be released both into the mitochondrial matrix{{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 | pmid=23604868 | pmc=3455268}}{{cite journal | vauthors = 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 | doi-access = free }} and into the intermembrane space, where it can then reach the cytosol.{{cite journal | vauthors = 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}} This could be explained by the fact that Complex III might produce superoxide as membrane permeable HOO^• rather than as membrane impermeable superoxide.

{{cleanup section|reason=Should get merged into table above|date=December 2023}}

• MT-CYB: mtDNA encoded cytochrome b; mutations associated with exercise intolerance
• CYC1: cytochrome c1
• CYCS: cytochrome c
• UQCRFS1: Rieske iron sulfur protein
• UQCRB: Ubiquinone binding protein, mutation linked with mitochondrial complex III deficiency nuclear type 3
• UQCRH: hinge protein
• UQCRC2: Core 2, mutations linked to mitochondrial complex III deficiency, nuclear type 5
• UQCRC1: Core 1
• UQCR: 6.4KD subunit
• UQCR10: 7.2KD subunit
• TTC19: Newly identified subunit, mutations linked to complex III deficiency nuclear type 2. Helps remove the N-terminal fragment of UQCRFS1, which would otherwise interfere with complex III function.{{cite journal |last1=Bottani |first1=E |last2=Cerutti |first2=R |last3=Harbour |first3=ME |last4=Ravaglia |first4=S |last5=Dogan |first5=SA |last6=Giordano |first6=C |last7=Fearnley |first7=IM |last8=D'Amati |first8=G |last9=Viscomi |first9=C |last10=Fernandez-Vizarra |first10=E |last11=Zeviani |first11=M |title=TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III. |journal=Molecular Cell |date=6 July 2017 |volume=67 |issue=1 |pages=96–105.e4 |doi=10.1016/j.molcel.2017.06.001 |pmid=28673544|doi-access=free }}

Mutations in complex III-related genes typically manifest as exercise intolerance.{{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 | s2cid = 29140366 | url = http://www.bio.unipd.it/bam/PDF/13-3/03536DiMauro.pdf}}{{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 | s2cid = 5849380 }} Other mutations have been reported to cause septo-optic dysplasia{{cite journal | vauthors = 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| s2cid = 12425236 }} and multisystem disorders.{{cite journal | vauthors = 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 | s2cid = 8944744 }} 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.{{cite journal | vauthors = 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 | doi-access = free }}

The extent to which these various pathologies are due to bioenergetic deficits or overproduction of superoxide is presently unknown.

• Cellular respiration
• Photosynthetic reaction centre

File:Mitochondrial electron transport chain (annotated diagram).svg|ETC

{{reflist|33em}}

{{refbegin}}

• {{cite journal | doi = 10.1016/0005-2728(77)90099-8 | vauthors = 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 }}
• {{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 | doi=10.1016/0304-4173(76)90012-4| doi-access = free }}
• {{cite journal | vauthors = 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 }}

{{refend}}

• {{Webarchive |url=https://web.archive.org/web/20061009122244/http://sb20.lbl.gov/cytbc1/ |date=October 9, 2006 |title=cytochrome bc₁ complex site (Edward A. Berry)}} at lbl.gov
• [http://www.life.uiuc.edu/crofts/bc-complex_site cytochrome bc₁ complex site (Antony R. Crofts)] {{Webarchive|url=https://web.archive.org/web/20070917062619/http://www.life.uiuc.edu/crofts/bc-complex_site |date=2007-09-17 }} at uiuc.edu
• {{Webarchive |url=https://archive.today/19990827002106/http://metallo.scripps.edu/PROMISE/CYTBC1.html |date=August 27, 1999 |title=PROMISE Database: cytochrome bc₁ complex}} at scripps.edu
• {{Webarchive |url=https://web.archive.org/web/20090112035125/http://www2.ufp.pt/~pedros/anim/2frame-iiien.htm |date=January 12, 2009 |title=Interactive Molecular Model of Complex III}} (Requires [https://web.archive.org/web/20060320002451/http://www.mdl.com/products/framework/chime/ MDL Chime])
• {{UMichOPM|families|superfamily|3}} - Calculated positions of bc1 and related complexes in membranes
• {{MeshName|Coenzyme+Q-Cytochrome-c+Reductase}}
• [https://www.omim.org/entry/124000 #124000 MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1; MC3DN1] on OMIM; lists all other types of complex III deficiency

{{Electron transport chain}}

{{Proton pumps}}

{{Mitochondrial DNA}}

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Category:EC 7.1.1

Category:Enzymes of known structure

Category:Cellular respiration

Category:Iron–sulfur proteins

Category:Transmembrane proteins