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Coenzyme Q – cytochrome c reductase

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Cytochrome b-c1 complex
Crystal structure of mitochondrial cytochrome bc complex bound with ubiquinone.[1]
Identifiers
Symbol(N/A)
SCOP21be3 / SCOPe / SUPFAM
TCDB3.D.3
OPM superfamily92
OPM protein3cx5
Membranome258
ubiquinol—cytochrome-c reductase
Identifiers
EC no.7.1.1.8
CAS no.9027-03-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

The coenzyme Q : cytochrome c – oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain (EC 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 bacteria. Mutations in Complex III cause exercise intolerance as well as multisystem disorders. The bc1 complex contains 11 subunits, 3 respiratory subunits (cytochrome B, cytochrome C1, Rieske protein), 2 core proteins and 6 low-molecular weight proteins.

Ubiquinol—cytochrome-c reductase catalyzes the chemical reaction

QH2 + 2 ferricytochrome c Q + 2 ferrocytochrome c + 2 H+

Thus, the two substrates of this enzyme are quinol (QH2) and ferri- (Fe3+) cytochrome c, whereas its 3 products are quinone (Q), ferro- (Fe2+) cytochrome c, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on diphenols and related substances as donor with a cytochrome as acceptor. This enzyme participates in oxidative phosphorylation. It has four cofactors: cytochrome c1, cytochrome b-562, cytochrome b-566, and a 2-Iron ferredoxin of the Rieske type.

Nomenclature

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

  • coenzyme Q-cytochrome c reductase,
  • dihydrocoenzyme Q-cytochrome c reductase,
  • reduced ubiquinone-cytochrome c reductase, complex III,
  • (mitochondrial electron transport),
  • ubiquinone-cytochrome c reductase,
  • ubiquinol-cytochrome c oxidoreductase,
  • reduced coenzyme Q-cytochrome c reductase,
  • ubiquinone-cytochrome c oxidoreductase,
  • reduced ubiquinone-cytochrome c oxidoreductase,
  • mitochondrial electron transport complex III,
  • ubiquinol-cytochrome c-2 oxidoreductase,
  • ubiquinone-cytochrome b-c1 oxidoreductase,
  • ubiquinol-cytochrome c2 reductase,
  • ubiquinol-cytochrome c1 oxidoreductase,
  • CoQH2-cytochrome c oxidoreductase,
  • ubihydroquinol:cytochrome c oxidoreductase,
  • coenzyme QH2-cytochrome c reductase, and
  • QH2:cytochrome c oxidoreductase.

Structure

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Structure of complex III (click to enlarge)

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.[2] Three subunits have prosthetic groups. The cytochrome b subunit has two b-type hemes (bL and bH), 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​

Composition of complex

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In vertebrates the bc1 complex, or Complex III, contains 11 subunits: 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.[3][4] Proteobacterial complexes may contain as few as three subunits.[5]

Table of subunit composition of complex III

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No. Subunit name Human gene symbol Protein description from UniProt Pfam family with Human protein
Respiratory subunit proteins
1 MT-CYB / Cyt b MT-CYB Cytochrome b Pfam PF13631
2 CYC1 / Cyt c1 CYC1 Cytochrome c1, heme protein, mitochondrial Pfam PF02167
3 Rieske / UCR1 UQCRFS1 Cytochrome b-c1 complex subunit Rieske, mitochondrial EC 1.10.2.2 Pfam PF02921 , Pfam PF00355
Core protein subunits
4 QCR1 / SU1 UQCRC1 Cytochrome b-c1 complex subunit 1, mitochondrial Pfam PF00675, Pfam PF05193
5 QCR2 / SU2 UQCRC2 Cytochrome b-c1 complex subunit 2, mitochondrial Pfam PF00675, Pfam PF05193
Low-molecular weight protein subunits
6 QCR6 / SU6 UQCRH Cytochrome b-c1 complex subunit 6, mitochondrial Pfam PF02320
7 QCR7 / SU7 UQCRB Cytochrome b-c1 complex subunit 7 Pfam PF02271
8 QCR8 / SU8 UQCRQ Cytochrome b-c1 complex subunit 8 Pfam PF02939
9 QCR9 / SU9 UQCRFS1a (N-terminal of Rieske, no separate entry) Pfam PF09165
10 QCR10 / SU10 UQCR10 Cytochrome b-c1 complex subunit 9 Pfam PF05365
11 QCR11 / SU11 UQCR11 Cytochrome b-c1 complex subunit 10 Pfam PF08997
  • 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.

Reaction

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schematic illustration of complex III reactions

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 (FeIII) + 2 H+
in → Q + 2 cytochrome c (FeII) + 4 H+
out

In the process called Q cycle,[6][7] 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.

Reaction mechanism

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The Q cycle

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 BL 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 BL heme to the BH Heme.
  4. Cytochrome c1 transfers its electron to cytochrome c (not to be confused with cytochrome c1), and the BH 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 BL 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 BL heme to the BH 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 BH heme, along with two protons from the matrix.
  5. The second ubiquinol (now oxidised to ubiquinone), along with the newly formed ubiquinol are released.[8]

Inhibitors of complex III

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There are three distinct groups of Complex III inhibitors.

  • Antimycin A binds to the Qi site and inhibits the transfer of electrons in Complex III from heme bH to oxidized Q (Qi site inhibitor).
  • Myxothiazol and stigmatellin binds to the Qo 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 Qo 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 have been commercialized as insecticides (IRAC group 20).[9]

Also propylhexedrine inhibits cytochrome c reductase.[10]

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).[11] Electron leakage occurs mainly at the Qo site and is stimulated by antimycin A. Antimycin A locks the b hemes in the reduced state by preventing their re-oxidation at the Qi site, which, in turn, causes the steady-state concentrations of the Qo 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.[12] Superoxide produced at the Qo site can be released both into the mitochondrial matrix[13][14] and into the intermembrane space, where it can then reach the cytosol.[13][15] This could be explained by the fact that Complex III might produce superoxide as membrane permeable HOO• rather than as membrane impermeable O−.
2.[14]

Human gene names

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  • 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.[16]

Mutations in complex III genes in human disease

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Mutations in complex III-related genes typically manifest as exercise intolerance.[17][18] Other mutations have been reported to cause septo-optic dysplasia[19] and multisystem disorders.[20] 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.[21]

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

See also

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Additional images

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  • ETC
    ETC

References

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  1. ^ PDB: 1ntz​; Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA, Xia D (August 2003). "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". Biochemistry. 42 (30): 9067–80. doi:10.1021/bi0341814. PMID 12885240.
  2. ^ Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK (July 1998). "Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex". Science. 281 (5373): 64–71. Bibcode:1998Sci...281...64I. doi:10.1126/science.281.5373.64. PMID 9651245.
  3. ^ Zhang Z, Huang L, Shulmeister VM, Chi YI, Kim KK, Hung LW, et al. (1998). "Electron transfer by domain movement in cytochrome bc1". Nature. 392 (6677): 677–84. Bibcode:1998Natur.392..677Z. doi:10.1038/33612. PMID 9565029. S2CID 4380033.
  4. ^ Hao GF, Wang F, Li H, Zhu XL, Yang WC, Huang LS, et al. (2012). "Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex". J Am Chem Soc. 134 (27): 11168–76. doi:10.1021/ja3001908. PMID 22690928.
  5. ^ Yang XH, Trumpower BL (1986). "Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans". J Biol Chem. 261 (26): 12282–9. doi:10.1016/S0021-9258(18)67236-9. PMID 3017970.
  6. ^ Kramer DM, Roberts AG, Muller F, Cape J, Bowman MK (2004). "Q-Cycle Bypass Reactions at the Qo Site of the Cytochrome bc1 (And Related) Complexes". Quinones and Quinone Enzymes, Part B. Methods in Enzymology. Vol. 382. pp. 21–45. doi:10.1016/S0076-6879(04)82002-0. ISBN 978-0-12-182786-1. PMID 15047094.
  7. ^ Crofts AR (2004). "The cytochrome bc1 complex: function in the context of structure". Annu. Rev. Physiol. 66: 689–733. doi:10.1146/annurev.physiol.66.032102.150251. PMID 14977419.
  8. ^ Ferguson SJ, Nicholls D, Ferguson S (2002). Bioenergetics (3rd ed.). San Diego: Academic. pp. 114–117. ISBN 978-0-12-518121-1.
  9. ^ Jeschke, Peter; Witschel, Matthias; Krämer, Wolfgang; Schirmer, Ulrich (25 January 2019). "32.3 Inhibitors of Mitochondrial Electron Transport: Acaricides and Insecticides". Modern Crop Protection Compounds (3rd ed.). Wiley‐VCH. pp. 1156–1201. ISBN 9783527699261.{{cite book}}: CS1 maint: date and year (link)
  10. ^ Holmes, J. H.; Sapeika, N; Zwarenstein, H (1975). "Inhibitory effect of anti-obesity drugs on NADH dehydrogenase of mouse heart homogenates". Research Communications in Chemical Pathology and Pharmacology. 11 (4): 645–6. PMID 241101.
  11. ^ Muller, F. L.; Lustgarten, M. S.; Jang, Y.; Richardson, A. & Van Remmen, H. (2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558.
  12. ^ Skulachev VP (May 1996). "Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants". Q. Rev. Biophys. 29 (2): 169–202. doi:10.1017/s0033583500005795. PMID 8870073. S2CID 40859585.
  13. ^ a b Muller F (2000). "The nature and mechanism of superoxide production by the electron transport chain: Its relevance to aging". AGE. 23 (4): 227–253. doi:10.1007/s11357-000-0022-9. PMC 3455268. PMID 23604868.
  14. ^ a b Muller FL, Liu Y, Van Remmen H (November 2004). "Complex III releases superoxide to both sides of the inner mitochondrial membrane". J. Biol. Chem. 279 (47): 49064–73. doi:10.1074/jbc.M407715200. PMID 15317809.
  15. ^ Han D, Williams E, Cadenas E (January 2001). "Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space". Biochem. J. 353 (Pt 2): 411–6. doi:10.1042/0264-6021:3530411. PMC 1221585. PMID 11139407.
  16. ^ Bottani, E; Cerutti, R; Harbour, ME; Ravaglia, S; Dogan, SA; Giordano, C; Fearnley, IM; D'Amati, G; Viscomi, C; Fernandez-Vizarra, E; Zeviani, M (6 July 2017). "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III". Molecular Cell. 67 (1): 96–105.e4. doi:10.1016/j.molcel.2017.06.001. PMID 28673544.
  17. ^ DiMauro S (November 2006). "Mitochondrial myopathies" (PDF). Curr Opin Rheumatol. 18 (6): 636–41. doi:10.1097/01.bor.0000245729.17759.f2. PMID 17053512. S2CID 29140366.
  18. ^ DiMauro S (June 2007). "Mitochondrial DNA medicine". Biosci. Rep. 27 (1–3): 5–9. doi:10.1007/s10540-007-9032-5. PMID 17484047. S2CID 5849380.
  19. ^ Schuelke M, Krude H, Finckh B, Mayatepek E, Janssen A, Schmelz M, Trefz F, Trijbels F, Smeitink J (March 2002). "Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation". Ann. Neurol. 51 (3): 388–92. doi:10.1002/ana.10151. PMID 11891837. S2CID 12425236.
  20. ^ Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J (October 2001). "Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene". Ann. Neurol. 50 (4): 540–3. doi:10.1002/ana.1224. PMID 11601507. S2CID 8944744.
  21. ^ Fisher N, Castleden CK, Bourges I, Brasseur G, Dujardin G, Meunier B (March 2004). "Human disease-related mutations in cytochrome b studied in yeast". J. Biol. Chem. 279 (13): 12951–8. doi:10.1074/jbc.M313866200. PMID 14718526.

Further reading

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