Wednesday, July 23, 2008

The bc1-complex for electron transfer from dihydroubiquinone to cytochrome c through the Q-cycle.

The bc1-like complexes (Complex III in mitochondria) play a central role in the electron transport chains of respiratory and photosynthetic machinery.

Their function is to carry out a sequence of electron and proton transfer reactions to generate a trans-membrane proton motive force that supplies the energy for ATP synthesizing utilizing the ATP synthase (excellent video, funny clip) machinery. Protons and electrons are supplied by dihydroubiquinone which in turn is generated by complexes I and II of the electron transport chain.

How do the bc1-like complexes carry out their function?
First the structure:
Figure 1: Bc1-complex
The cyt bc1-complex contains two separate redox chains; High potential and low potential.
The high-potential chain connects the Qo-binding site with the cyt c1 through the Rieske Iron-sulphur-protein (RISP). The RISP is situated on a rotateable arm that is able to connect the cyt c1 component with the Qo-binging site.
The low potential chain connects the Qo-site with the Q1-site through the cyt BL and Cyt BH complexes.

Now the mechanism. A bifurcated electron transfer mechanism:
Figure 2: Bifurcated electron transfer the Qo-site of the bc1-complex.

1) The lipid-soluble dihydroubiquinone molecule binds at the Qo-site and liberates one proton into the intermembrane space and in the process forms a semiubiquinone radical.
2) The RISP swings around to receives an electron from the semiubiquinone and donates it to cyt c1 which in turn donates it to cytochrome c. Cytochrome c plays its part in energy transfer to complex IV of the electron transfer chain.
3) A second proton is liberates into the intermembrane space and an electron is donated to the low potential chain, resulting in the formation of ubiquinone
4) At the Q1-site the electron is donated to ubiquinone to form semiubiquinone, while a proton is donated from the mitochondrial matrix.
5) In order for the formation of dihydroubiquinone at the Q1-site, two dihydroubiquinones must bins at the Qo-site.
6) Thus the end result is the formation of 1 dihydroubiquinone, 2 quinones, 4 intermembrane protons and 2 ferrocyrochrome c proteins and loss of 2 mitochondrial matrix molecules after the binding of 2 dihydroubiquinones at the Qo-site.

That is the basic general mechanism, however research is ongoing into how bypass reactions are avoided.
For example:
Why do the electrons flow in only one direction in the low electron transport chains?
Why aren't both electrons donated to the high-potential chain in the first place?
Radical hypotheses have been proposed including (From Cape et al. 2006 Trends Plant Sci. 2006 Jan;11(1):46-55.):
(i) A complex that can either stabilize the intermediate semiubiquinone, rendering it inert and invisible through some unknown mechanism, or that can use the unprecedented tactic of destabilizing its reactive intermediates.
(ii) A kinetic ‘water-park’ that tunes reaction activation enthalpies or entropies to route ‘water’ (electron) flow into productive channels.
(iii) A nano-machine that gates the electron and proton transfer reactions of semiubiquinone according to its recognition of the different redox and/or conformational states of the complex.
(iv) An extraordinary, and unprecedented, double concerted oxidation of dihydroubiquinone that simultaneously distributes two electrons and at least one proton between at least three different acceptors.
Options II and III do not exclude the possibility of quantum mechanics and coulombic interactions playing a role.

All-in-all a brilliant solution for a bifurcated electron transfer mechanism in order to generate a proton motive force from dihydroubiquinone.

Interestingly, the intermediate (semiubiquinone) generated at the Qo-site is believed to be a major contributor to the formation of reactive oxygen species by donating it's free electron to oxygen and thereby resulting in the formation of superoxide. Superoxide formation causes damage to various molecules including DNA, RNA, proteins and lipids.

Figure 3: Semiubiquinone

Paradoxically though, reactive oxygen specie generation at the Qo-site as a result of semiubiquinone formation is increased during periods of hypoxia (low oxygen). Hypoxia is a major initiator of cancerous growth because it activates various pro-growth signaling pathways. Hypoxia in cells usually occur as a result of poor circulation and delivery of oxygen. Obesity, lack of exercise and poor diet all contribute to these circumstances.

Thus, the bc1-complexes connects bad health choices with higher incidences of cancers and other mitochondrially related diseases through reactive oxygen species formation as a result of hypoxic conditions within various systems of the body.

Exercising and eating right are good for oiling your biomolecular machines. :)

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