| UCR_TM |
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Crystal structure of mitochondrial cytochrome bc1 complex bound with ubiquinone.[1]
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| Identifiers |
| Symbol |
UCR_TM |
| Pfam |
PF02921 |
| InterPro |
IPR004192 |
| SCOP |
1be3 |
| SUPERFAMILY |
1be3 |
| TCDB |
3.D.3 |
| OPM superfamily |
345 |
| OPM protein |
3cx5 |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
| ubiquinol—cytochrome-c reductase |
| Identifiers |
| EC number |
1.10.2.2 |
| CAS number |
9027-03-6 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Gene Ontology |
AmiGO / EGO |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
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schematic illustration of complex III reactions
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 eubacteria. 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.
Contents
- 1 Nomenclature
- 2 Structure
- 3 Composition of Complex
- 3.1 Table of Subunit composition of Complex III
- 4 Reaction
- 5 Reaction mechanism
- 6 Inhibitors of complex III
- 7 Oxygen free radicals
- 8 Human gene names
- 9 Mutations in Complex III genes in human disease
- 10 See also
- 11 Additional images
- 12 References
- 13 Further reading
- 14 External links
Nomenclature
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,
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- 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.
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Structure
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
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
| No. |
Subunit name |
Human protein |
Protein description from UniProt |
Pfam family with Human protein |
| Respiratory subunit proteins |
| 1 |
MT-CYB / Cyt b |
CYB_HUMAN |
Cytochrome b |
Pfam PF13631 |
| 2 |
CYC1 / Cyt c1 |
CY1_HUMAN |
Cytochrome c1, heme protein, mitochondrial |
Pfam PF02167 |
| 3 |
Rieske / UCR1 |
UCRI_HUMAN |
Cytochrome b-c1 complex subunit Rieske, mitochondrial EC 1.10.2.2 |
Pfam PF02921 , Pfam PF00355 |
| Core protein subunits |
| 4 |
QCR1 / SU1 |
QCR1_HUMAN |
Cytochrome b-c1 complex subunit 1, mitochondrial |
Pfam PF00675, Pfam PF05193 |
| 5 |
QCR2 / SU2 |
QCR2_HUMAN |
Cytochrome b-c1 complex subunit 2, mitochondrial |
Pfam PF00675, Pfam PF05193 |
| Low-molecular weight protein subunits |
| 6 |
QCR6 / SU6 |
QCR6_HUMAN |
Cytochrome b-c1 complex subunit 6, mitochondrial |
Pfam PF02320 |
| 7 |
QCR7 / SU7 |
QCR7_HUMAN |
Cytochrome b-c1 complex subunit 7 |
Pfam PF02271 |
| 8 |
QCR8 / SU8 |
QCR8_HUMAN |
Cytochrome b-c1 complex subunit 8 |
Pfam PF02939 |
| 9 |
QCR9 / SU9 / UCRC |
QCR9_HUMANa |
Cytochrome b-c1 complex subunit 9 |
Pfam PF09165 |
| 10 |
QCR10 / SU10 |
QCR10_HUMAN |
Cytochrome b-c1 complex subunit 10 |
Pfam PF05365 |
| 11 |
QCR11 / SU11 |
QCR11_HUMAN |
Cytochrome b-c1 complex subunit 11 |
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
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
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 c1 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:
- Cytochrome b binds a ubiquinol and a ubiquinone.
- The 2Fe/2S center and BL heme each pull an electron off the bound ubiquinol, releasing two hydrogens into the intermembrane space.
- One electron is transferred to cytochrome c1 from the 2Fe/2S centre, whilst another is transferred from the BL heme to the BH Heme.
- 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.
- Cytochrome c diffuses. The first ubiquinol (now oxidised to ubiquinone) is released, whilst the semiquinone remains bound.
Round 2:
- A second ubiquinol is bound by cytochrome b.
- The 2Fe/2S center and BL heme each pull an electron off the bound ubiquinol, releasing two hydrogens into the intermembrane space.
- One electron is transferred to cytochrome c1 from the 2Fe/2S centre, whilst another is transferred from the BL heme to the BH Heme.
- Cytocrome c1 then transfers its electron to cytochrome c, whilst the nearby semiquinone picks up a second electron from the BH heme, along with two protons from the matrix.
- The second ubiquinol (now oxidised to ubiquinone), along with the newly formed ubiquinol are released.[8]
Inhibitors of complex III
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).
Also propylhexedrine inhibits cytochrome c reductase.[9]
Oxygen free radicals
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).[10] 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.[11] Superoxide produced at the Qo site can be released both into the mitochondrial matrix[12][13] and into the intermembrane space (from where it can reach the cytosol.[12][14] This could be explained by the fact that Complex III might produce superoxide as membrane permeable HOO• rather than as membrane impermeable O2-..[13]
Human gene names
MTCYB: 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
Mutations in Complex III genes in human disease
Mutations in Complex III-related genes typically manifest as exercise intolerance.[15][16] Other mutations have been reported to cause septo-optic dysplasia[17] and multisystem disorders.[18] 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.[19]
The extent to which these various pathologies are due to bioenergetic deficits or overproduction of superoxide is presently unknown.
See also
- Cellular respiration
- Photosynthetic reaction centre
Additional images
References
- ^ 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.
- ^ 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. doi:10.1126/science.281.5373.64. PMID 9651245.
- ^ 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. doi:10.1038/33612. PMID 9565029.
- ^ 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.
- ^ Yang XH, Trumpower BL. (1986). "Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from Paracoccus denitrificans". J Biol Chem. 261: 12282–9. PMID 3017970.
- ^ 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". Meth. Enzymol. Methods in Enzymology 382: 21–45. doi:10.1016/S0076-6879(04)82002-0. ISBN 978-0-12-182786-1. PMID 15047094.
- ^ 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.
- ^ Ferguson SJ, Nicholls D, Ferguson S (2002). Bioenergetics (3rd ed.). San Diego: Academic. pp. 114–117. ISBN 0-12-518121-3.
- ^ 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.
- ^ Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and 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.
- ^ 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.
- ^ 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. PMID 23604868.
- ^ 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.
- ^ 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.
- ^ DiMauro S (November 2006). "Mitochondrial myopathies". Curr Opin Rheumatol 18 (6): 636–41. doi:10.1097/01.bor.0000245729.17759.f2. PMID 17053512.
- ^ DiMauro S (June 2007). "Mitochondrial DNA medicine". Biosci. Rep. 27 (1–3): 5–9. doi:10.1007/s10540-007-9032-5. PMID 17484047.
- ^ 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.
- ^ 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.
- ^ 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
- Marres CM, Slater EC (1977). "Polypeptide composition of purified QH2:cytochrome c oxidoreductase from beef-heart mitochondria". Biochim. Biophys. Acta 462 (3): 531–548. doi:10.1016/0005-2728(77)90099-8. PMID 597492.
- Rieske JS (1976). "Composition, structure, and function of complex III of the respiratory chain". Biochim. Biophys. Acta 456 (2): 195–247. doi:10.1016/0304-4173(76)90012-4. PMID 788795.
- Wikstrom M, Krab K, Saraste M (1981). "Proton-translocating cytochrome complexes". Annu. Rev. Biochem. 50: 623–655. doi:10.1146/annurev.bi.50.070181.003203. PMID 6267990.
External links
- cytochrome bc1 complex site (Edward A. Berry) at lbl.gov
- cytochrome bc1 complex site (Antony R. Crofts) at uiuc.edu
- PROMISE Database: cytochrome bc1 complex at scripps.edu
- Interactive Molecular Model of Complex III (Requires MDL Chime)
- UMich Orientation of Proteins in Membranes families/superfamily-3 - Calculated positions of bc1 and related complexes in membranes
- Coenzyme Q-Cytochrome-c Reductase at the US National Library of Medicine Medical Subject Headings (MeSH)
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Metabolism: Citric acid cycle enzymes
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| Cycle |
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- Oxoglutarate dehydrogenase
- Succinyl CoA synthetase
- Succinate dehydrogenase (SDHA)
- Fumarase
- Malate dehydrogenase and ETC
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| Anaplerotic |
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to acetyl-CoA
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- Pyruvate dehydrogenase complex (E1, E2, E3)
- (regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase)
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to α-ketoglutaric acid
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to succinyl-CoA
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to oxaloacetate
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- Pyruvate carboxylase
- Aspartate transaminase
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Mitochondrial
electron transport chain/
oxidative phosphorylation |
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Primary
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- Complex I/NADH dehydrogenase
- Complex II/Succinate dehydrogenase
- Coenzyme Q
- Complex III/Coenzyme Q - cytochrome c reductase
- Cytochrome c
- Complex IV/Cytochrome c oxidase
- Coenzyme Q10 synthesis: COQ2
- COQ3
- COQ4
- COQ5
- COQ6
- COQ7
- COQ9
- COQ10A
- COQ10B
- PDSS1
- PDSS2
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Other
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- Alternative oxidase
- Electron-transferring-flavoprotein dehydrogenase
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Ion pump: proton pumps: Oxidoreduction-driven transporters (TC 3D)
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| ETC |
- ETC Complex I
- ETC Complex III
- ETC Complex IV
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| Other |
- Cytochrome b6f complex
- Inorganic pyrophosphatase
- V-ATPase
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Mitochondrial proteins
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| Outer membrane |
| fatty acid degradation |
- Carnitine palmitoyltransferase I
- Long-chain-fatty-acid—CoA ligase
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| tryptophan metabolism |
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monoamine neurotransmitter
metabolism |
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| Intermembrane space |
- Adenylate kinase
- Creatine kinase
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| Inner membrane |
| oxidative phosphorylation |
- Coenzyme Q – cytochrome c reductase
- Cytochrome c
- NADH dehydrogenase
- Succinate dehydrogenase
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| pyrimidine metabolism |
- Dihydroorotate dehydrogenase
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| mitochondrial shuttle |
- Malate-aspartate shuttle
- Glycerol phosphate shuttle
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| other |
- Glutamate aspartate transporter
- Glycerol-3-phosphate dehydrogenase
- ATP synthase
- Carnitine palmitoyltransferase II
- Uncoupling protein
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| Matrix |
| citric acid cycle |
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- Oxoglutarate dehydrogenase complex
- Succinyl coenzyme A synthetase
- Fumarase
- Malate dehydrogenase
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| anaplerotic reactions |
- Aspartate transaminase
- Glutamate dehydrogenase
- Pyruvate dehydrogenase complex
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| urea cycle |
- Carbamoyl phosphate synthetase I
- Ornithine transcarbamylase
- N-Acetylglutamate synthase
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| alcohol metabolism |
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| Other/to be sorted |
| steroidogenesis |
- Cholesterol side-chain cleavage enzyme
- Steroid 11-beta-hydroxylase
- Aldosterone synthase
- Frataxin
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- Mitochondrial membrane transport protein
- Mitochondrial permeability transition pore
- Mitochondrial carrier
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| Mitochondrial DNA |
| Complex I |
- MT-ND1
- MT-ND2
- MT-ND3
- MT-ND4
- MT-ND4L
- MT-ND5
- MT-ND6
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| Complex III |
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| Complex IV |
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| ATP synthase |
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| tRNA |
- MT-TA
- MT-TC
- MT-TD
- MT-TE
- MT-TF
- MT-TG
- MT-TH
- MT-TI
- MT-TK
- MT-TL1
- MT-TL2
- MT-TM
- MT-TN
- MT-TP
- MT-TQ
- MT-TR
- MT-TS1
- MT-TS2
- MT-TT
- MT-TV
- MT-TW
- MT-TY
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see also mitochondrial diseases
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Oxidoreductases: diphenol family (EC 1.10)
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| 1.10.1 |
- Trans-acenaphthene-1,2-diol dehydrogenase
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| 1.10.2 |
- Coenzyme Q - cytochrome c reductase
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| 1.10.3 |
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| 1.10.99 |
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| Other |
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Enzymes
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| Activity |
- Active site
- Binding site
- Catalytic triad
- Oxyanion hole
- Enzyme promiscuity
- Catalytically perfect enzyme
- Coenzyme
- Cofactor
- Enzyme catalysis
- Enzyme kinetics
- Lineweaver–Burk plot
- Michaelis–Menten kinetics
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| Regulation |
- Allosteric regulation
- Cooperativity
- Enzyme inhibitor
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| Classification |
- EC number
- Enzyme superfamily
- Enzyme family
- List of enzymes
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| Types |
- EC1 Oxidoreductases(list)
- EC2 Transferases(list)
- EC3 Hydrolases(list)
- EC4 Lyases(list)
- EC5 Isomerases(list)
- EC6 Ligases(list)
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