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 (), 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

Structure of complex III

Structures of complex III: ,

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 (Fe^III) + 2 H⁺_in ? Q + 2 cytochrome c (Fe^II) + 4 H⁺_out

In the process called Q cycle,^[2][3] 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 Q cycle

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.^[4]

Inhibitors of complex III

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 pockets within the Q_o 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 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 ^[5]. Superoxide produced at the Qo site can be released both into the mitochondrial matrix ^[6][7] and intermembrane space (from where it can reach the cytosol ^[8][9]). This could be explained by the fact that Complex III might produce superoxide as membrane permeable HO2 rather than as membrane impermeable O2- ^[10].

Mutations in Complex III genes in human disease

Mutations in Complex III related genes, typically manifest as exercise intolerance ^[11][12]. Other mutations have been reported to cause septo-optic displaisa ^[13] and mutlisystem disorders^[14] . 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 ^[15].

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

References

See also

• Cellular respiration
• Photosynthetic reaction centre
• Complex 3

Additional images

<gallery> Image:ETC.PNG|ETC Image:Etc2.png|ETC </gallery>

External links

• cytochrome ''bc''₁ complex site (Edward A. Berry) at lbl.gov
• cytochrome ''bc''₁ complex site (Antony R. Crofts) at uiuc.edu
• PROMISE Database: cytochrome ''bc''₁ complex at scripps.edu
• Interactive Molecular Model of Complex III (Requires MDL Chime)
• - Calculated positions of bc1 and related complexes in membranes

de:Cytochrom-c-Reduktase fr:Coenzyme Q - cytochrome c-réductase it:Ubichinolo-citocromo c reduttasi pl:Cytochrom bc1 pt:Coenzima Q-citocromo c redutase

---

Source: Wikipedia | The above article is available under the GNU FDL. | Edit this article