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Tuesday, January 23, 2007

Ubiquinone and the Proton Pump

Yesterday's molecule was ubiquinone, also known as coenzyme Q or just plain "Q." Ubiquinone is a lipid soluble cofactor that accepts and donates electrons in oxidation-reduction reactions. These are reactions in which electrons are transferred from one molecule (oxidation) and accepted by another (reduction).

Ubiquinone is confined to lipid membranes where it diffuses laterally. It is synthesized in reactions catalyzed by membrane-bound enzymes. Bacteria contain a structurally similar molecule called menaquinone and photosynthetic organisms have plastoquinone.

All of these quinones play a role in pumping proteins across a membrane in order to create a proton gradient that's used to make ATP. If you understand how this works then you can understand how life first arose 3.5 billion years ago.
Quinones can carry up to two electrons per molecule and they are added one-at-a-time in the reaction shown below.

The reason why ubiquinone is so important is because the ring structure stabilizes the negatively charged semiquinone anion allowing for the addition of another electron to create ubiquinol (QH2). Note that when two electrons are taken up, two protons (H+) are added to neutralize the negative charge. In the reverse reaction (ubiquinol to ubiquinone: bottom to top) two protons are released when the electrons are given up.

The key to understanding the importance of ubiquinone is recognizing that protons can be taken up from one side of the membrane during the reduction of ubiquinone and they can be released on the other side of the membrane when ubiquinol is oxidized in the reverse reaction.

The enzymes responsible for this differential uptake and release are part of the membrane-associated electron transport chain found in mitochondria and in the membranes of bacteria. There are several different reactions that take place as shown in the simple schematic diagram below.

The red line traces the path of electrons released from a molecule called NADH. The electrons pass through three different membrane complexes called complex I, complex III, and complex IV. At each step, protons are pumped across the membrane. In complex IV the electrons are passed to oxygen (O2) to make water. This final step is why you need oxygen to live.

We are mostly interested in the middle complex (complex III) because that's the one found in all species. It also takes part in photosynthesis, which is a similar process for producing a proton gradient.

The protons accumulate in the intermembrane space between the outer and inner membranes of mitochondria and bacteria. The complexes are located in the inner membrane. (The outer membrane isn't shown in the diagram.) Because there's a higher concentration of protons in the intermembrane space compared to inside the cell, there's pressure to return protons down the concentration gradient to restore the balance. This pressure is called the protonmotive force. It's used to drive ATP synthesis by coupling the transport of protons to the phosphorylation of ADP. ATP is the main energy currency in the cell. It can be used to make other molecules or cause muscles to contract etc.

The idea that electron transport is mainly used to create a proton gradient which is then used up in the synthesis of ATP is known as the Chemiosmotic Theory. It was championed in the 1960's by Peter Mitchell (see tomorrow's Nobel Laureate).

The role of quinone in complex III is complicated. Here's a schematic (left) showing the uptake of protons (H+) from the cytoplasmic side (bottom) to form QH2 and their release on the other side when QH2 is converted back to Q. This complicated set of reactions is known as the Q cycle and it is responsible for the generation of protonmotive force in all species. Since the protonmotive force is what drives ATP synthesis, this makes the Q cycle one of the most important reactions in biochemistry.

The structure of complex III has been solved. In addition to being one of the most important enzymes, it is also one of the most beautiful. You can easily see the two b heme groups that form the catalytic sites for oxidation and reduction of QH2 and Q. The iron-sulfur center (Fe-S) helps in the transport of electrons to heme c1 and eventually to cytochrome c.

This is such a fabulous molecule that I put it on the cover of my biochemistry book.

Students often wonder how the earliest forms of life created energy before the invention of photosynthesis. Once you understand the Chemiosmotic Theory, it isn't difficult to see how this worked 3.5 billion years ago. All you need is a source of energetic electrons to drive the reduction of quinone. In the presence of a cytochrome complex, like complex III, you'll get a protonmotive force generated by the Q cycle. This will power ATP synthesis.

Here's a simplified version of how it's done in chemoautotrophic bacteria that can use hydrogen as an energy source. There are many other possible sources of energy, such as H2S or NH4+. They are obvious candidates for the kinds of energy production that was common when life first began.


James Redekop said...

You might find these pieces of molecule-based jewelery interesting.

Torbjörn Larsson said...

Thanks for sharing such a beautiful molecule as complex III!

Btw, why and how is many large proteins mirrorsymmetric, and even sometimes with active centers doubled like it seems complex III is (antibodies, et cetera)? I can't really see how simpler mechanisms like for example gene doubling and inversions makes the symmetry.