Coenzyme Q - cytochrome c reductase


Coenzyme Q - cytochrome c reductase

The coenzyme Q : cytochrome "c" — oxidoreductase, sometimes called the cytochrome "bc"1 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 lipoprotein 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.

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 [Iwata S., Lee J.W., Okada K., Lee J.K., Iwata M., Rasmussen B., Link T.A., Ramaswamy S., Jap B.K. (1998) Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science 281: 64-71] . 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 ("c"1), 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

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, [Kramer, D. M.; Roberts, A. G.; Muller, F.; Cape, J.; Bowman, M. K. Q-cycle bypass reactions at the Qo site of the cytochrome bc1 (and related) complexes. Methods Enzymol. 382:21-45; 2004. PMID 15047094] [Crofts, A.R. (2004). The cytochrome bc1 complex: function in the context of structure. Annu Rev Physiol. 66, 689-733. PMID 14977419] 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 named the Q cycle or the ubiquinone cycle as mentioned above. In this cycle four protons get released into the P or Positive side (inter membrane space) but only two protons get taken up from the N or Negative side (matrix), see animation to the right. As a result a proton gradient is formed across the membrane. Also, two ubiquinols get oxidized to ubiquinones and one ubiquinone gets reduced to ubiquinol! All this is accomplished by the transfer of two electrons from two ubiquinols to two cytochrome c's as well as two electrons from the same two ubiquinols to a ubiquinone. The reaction goes as follows.

1. Ubiquinol binds to cytochrome b.
2. The 2Fe/2S center and BL Heme each pull an electron off the bound ubiquinone, and two hydrogens are released into the intermembrane space.
3. The 2Fe/2S center transfers its electron to cytochrome c1 and the BL Heme transfers its electron to the BH Heme.
4. Cytocrome c1 transfers its electron to a water soluble cytochrome c (not to be confused with cytochrome c1 which is membrane bound), and the BH Heme transfers its electron to a nearby ubiquinone turning the ubiquinone into a ubisemiquinone.
5. Cytochrome c diffuses and the fully oxidized ubiquinone is released.
6. Another ubiquinol binds to cytochrome b.
7. The 2Fe/2S center and BL Heme each pull an electron off the bound ubiquinone and two hydrogens are released into the intermembrane space.
8. The 2Fe/2S center transfers its electron to cytochrome c1 and the BL Heme transfers its electron to the BH Heme.
9. Cytocrome c1 then transfers its electron to a water soluble cytochrome c, and the BH Heme transfers its electron as well as two hydrogens from the matrix to the nearby ubisemiquinone turning the ubisemiquinone into a ubiquinol.
10.The fully oxidized ubiquinone and ubiquinol are released. [Nicholls, David and Stuart Ferguson. Bioenergetics3. Acociate Press: San Diego, California 2002. pg 114-117]

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 "b"H 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 pockets within the Qo site.
** Myxothiazol binds very close to cytochrome bL (hence termed a "proximal" inhibitor).
** Stigmatellin binds near the Rieske Iron sulfur protein, with which it strongly interacts.

Some have been commercialized as fungicides (the strobilurin derivates) and as anti-malaria agents (atovaquone).

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). 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 [Skulachev, V. P. (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, 169-202] . Superoxide produced at the Qo site can be released both into the mitochondrial matrix [Muller, F. (2000) The Nature and Mechanism of Superoxide production by the Electron Transport Chain: Its relevance to aging. J. Amer. Aging Assoc. 23, 227-253] [Muller, F. L., Liu, Y. and Van Remmen, H. (2004) Complex III Releases superoxide to both sides of the inner mitochondrial membrane. J. Biol. Chem. 279, 49064-49073] and intermembrane space (from where it can reach the cytosol [Han, D., Williams, E. and Cadenas, E. (2001) Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem. J. 353, 411-416.] [Muller, F. (2000) The Nature and Mechanism of Superoxide production by the Electron Transport Chain: Its relevance to aging. J. Amer. Aging Assoc. 23, 227-253] ). This could be explained by the fact that Complex III might produce superoxide as membrane permeable HO2 rather than as membrane impermeable O2- [Muller, F. L., Liu, Y. and Van Remmen, H. (2004) Complex III Releases superoxide to both sides of the inner mitochondrial membrane. J. Biol. Chem. 279, 49064-49073] .

References

See also

*Cellular respiration
*Photosynthetic reaction centre
*Complex 3


=Additional

External links

* [http://sb20.lbl.gov/cytbc1 cytochrome "bc"1 complex site (Edward A. Berry)] at lbl.gov
* [http://www.life.uiuc.edu/crofts/bc-complex_site cytochrome "bc"1 complex site (Antony R. Crofts)] at uiuc.edu
* [http://metallo.scripps.edu/PROMISE/CYTBC1.html PROMISE Database: cytochrome "bc"1 complex] at scripps.edu
* [http://www.ufp.pt/~pedros/anim/2frame-iiien.htm Interactive Molecular Model of Complex III] (Requires [http://www.mdl.com/products/framework/chime/ MDL Chime] )
* - Calculated positions of bc1 and related complexes in membranes
*


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