Qvh

CoQH2-cytochrome c reductase (complex III)

CoQH2-cytochrome c reductase (complex III)

(outside)

Per 2 e transferred through complex III to cytochrome c, 4 H+ released to the intermembrane space

▲ FIGURE 8-21 The Q cycle. CoQH2 binds to the Qo site on the intermembrane space (outer) side of CoQ-cytochrome c reductase complex and CoQ binds to the Qi site on the matrix (inner) side. One electron from the CoQH2 bound to Qo travels directly to cytochrome c via an Fe-S cluster and cytochrome c1. The other electron moves through the b cytochromes to CoQ at the Qi site, forming the partially reduced semiquinone (Q—-). Simultaneously, CoQH2 releases its two protons into the intermembrane space. The CoQ now at the Qo site dissociates and a second CoQH2 binds there. As before, one electron moves directly to cytochrome c1 and the other to the Q— at the Qi site forming, together with two protons picked up from the matrix space, CoQH2, which then dissociates. The net result is that four protons are translocated from the matrix to the intermembrane space for each pair of electrons transported through the CoQH2-cytochrome c reductase complex (bottom). See the text for details. [Adapted from B. Trumpower, 1990, J. Biol. Chem. 265:11409, and E. Darrouzet et al., 2001, Trends Biochem. Sci. 26:445.]

electrons from CoQH2 is transported, via an iron-sulfur protein and cytochrome c1, directly to cytochrome c (step 2b). The other electron released from the CoQH2 moves through cytochromes bL and bH and partially reduces an oxidized CoQ molecule bound to the Q( site on the matrix (inner) side of the complex, forming a CoQ semiquinone anion Q_- (step 3).

After the loss of two protons and two electrons, the now oxidized CoQ at the Qo site dissociates (step 4), and a second CoQH2 binds to the site (step 5). As before, the bound CoQH2 releases two protons into the intermembrane space (step 6a), while simultaneously one electron from CoQH2 moves directly to cytochrome c (step 6b), and the other electron moves through the b cytochromes to the Q_- bound at the Q( site (step 7). There the addition of two protons from the matrix yields a fully reduced CoQH2 molecule at the Qi site (step 8). This CoQH2 molecule then dissociates from the CoQH2-cytochrome c reductase complex (step 9), freeing the Q( to bind a new molecule of CoQ (step 10) and begin the Q cycle over again.

In the Q cycle, two molecules of CoQH2 are oxidized to CoQ at the Qo site and release a total of four protons into the intermembrane space, but one molecule of CoQH2 is regenerated from CoQ at the Q( site (see Figure 8-21, bottom). Thus the net result of the Q cycle is that four protons are translocated to the intermembrane space for every two electrons transported through the CoQH2-cytochrome c reduc-tase complex and accepted by two molecules of cytochrome c. The translocated protons are all derived from the matrix, taken up either by the NADH-CoQ reductase complex or by the CoQH2-cytochrome c reductase complex during reduction of CoQ. While seemingly cumbersome, the Q cycle increases the numbers of protons pumped per pair of electrons moving through the CoQH2-cytochrome c reductase complex. The Q cycle is found in all plants and animals as well as in bacteria. Its formation at a very early stage of cellular evolution was likely essential for the success of all life-forms as a way of converting the potential energy in reduced coen-zyme Q into the maximum proton-motive force across a membrane.

Although the model presented in Figure 8-21 is consistent with a great deal of mutagenesis and spectroscopic studies on the CoQH2-cytochrome c reductase complex, it raises a number of questions. For instance, how are the two electrons released from CoQH2 at the Qo site directed to different acceptors (cytochromes c1 and bL)? Previous studies implicated an iron-sulfur (2Fe-2S) cluster in the transfer of electrons, one at a time, from CoQH2 at the Qo site to cytochrome c1. Yet the recently determined three-dimensional structure of the CoQH2-cytochrome c reductase complex, which is a dimeric protein, initially suggested that the 2Fe-2S cluster is positioned too far away from the Qo site for an electron to "jump" to it. Subsequently, researchers discovered that the subunit containing the 2Fe-2S cluster has a flexible hinge that permits it to exist in two conformational states

(Figure 8-22). In one conformation, the 2Fe-2S cluster is close enough to the Qo site to pick up an electron from CoQH2 bound there. Movement of the hinge then positions the 2Fe-2S cluster near enough to the heme on cytochrome c1 for electron transfer to occur. With the Fe-S subunit in this alternative conformation, the second electron released from CoQH2 bound to the Qo site cannot move to the 2Fe-2S cluster and has to take the less thermodynamically favored route to cytochrome bL.

Cyt c

Fe-S subunit conformation 2

Fe-S subunit conformation 1

Intermembrane space

Heme bL Heme bH

Heme c1 2Fe-2S 2Fe-2S

conformation 2 conformation 1

Cyt c

Fe-S subunit conformation 2

Fe-S subunit conformation 1

Intermembrane space

Heme bL Heme bH

Heme c1 2Fe-2S 2Fe-2S

conformation 2 conformation 1

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