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Chapter: Biochemistry: Electron Transport and Oxidative Phosphorylation

Organization of Electron Transport Complexes

What reactions take place in the respiratory complexes? What is the nature of the iron-containing proteins of electron transport?

Organization of Electron Transport Complexes

Intact mitochondria isolated from cells can carry out all the reactions of the electron transport chain; the electron transport apparatus can also be resolved into its component parts by a process called fractionation. Four separate respiratory complexes can be isolated from the inner mitochondrial membrane.These complexes are multienzyme systems. We encountered other examples of such multienzyme complexes, such as the pyruvate dehydrogenase complex and the α-ketoglutarate dehydrogenase complex. Each of the respiratory complexes can carry out the reactions of a portion of the electron transport chain.

What reactions take place in the respiratory complexes?

Complex I The first complex,NADH-CoQ oxidoreductase,catalyzes the firststeps of electron transport, namely the transfer of electrons from NADH to coenzyme Q (CoQ). This complex is an integral part of the inner mitochondrialmembrane and includes, among other subunits, several proteins that contain an iron–sulfur cluster and the flavoprotein that oxidizes NADH. (The total number of subunits is more than 20. This complex is a subject of active research, which has proven to be a challenging task because of its complexity. It is particularly difficult to generalize about the nature of the iron–sulfur clusters because they vary from species to species.) The flavoprotein has a flavin coenzyme, called flavin mononucleotide, or FMN, which differs from FAD in not having an adenine nucleotide (Figure 20.4).

The reaction occurs in several steps, with successive oxidation and reduction of the flavoprotein and the iron–sulfur moiety. The first step is the transfer of electrons from NADH to the flavin portion of the flavoprotein:

NADH + H+ + E—FMN - > NAD+ + E—FMNH2

in which the notation E—FMN indicates that the flavin is covalently bonded to the enzyme. In the second step, the reduced flavoprotein is reoxidized, and the oxidized form of the iron–sulfur protein is reduced. The reduced iron–sulfur protein then donates its electrons to coenzyme Q, which becomes reduced to CoQH2 (Figure 20.5). Coenzyme Q is also called ubiquinone. The equations for the second and third steps are shown here:

E—FMNH2 + 2Fe—Soxidized - > E—FMN + 2Fe—Sreduced + 2H+

2Fe—Sreduced + CoQ + 2H+ - > 2Fe—Soxidized + CoQH2

The notation Fe—S indicates the iron–sulfur clusters. The overall equation for the reaction is

NADH + H+ + CoQ - > NAD+ + CoQH2

This reaction is one of the three responsible for the proton pumping (Figure 20.6) that creates the pH (proton) gradient. The standard free-energy change ( ∆G°' = –81 kJ mol–1 = –19.4 kcal mol–1) indicates that the reaction is strongly exergonic, releasing enough energy to drive the phosphorylation of ADP to ATP (Figure 20.7). 

An important consideration about proton pumping and electron transport is the subtle differences between the electron carriers. Although they can all exist in an oxidized or reduced form, they reduce each other in a certain order. In other words, reduced NADH donates its electrons to coenzyme Q, but not the other way around. Thus, there is a direction to the electron flow in the complexes we will study.

The other important subtlety is that some carriers, such as NADH, carry electrons and hydrogens in their reduced forms; others, such as the iron– sulfur protein we just saw, can carry only electrons. This is the basis of the pro-ton pumping that ultimately leads to ATP production. When a carrier such as NADH reduces the iron–sulfur protein, it passes along its electrons, but not its hydrogens. The architecture of the inner mitochondrial membrane and the electron carriers allows the hydrogen ions to pass out on the opposite side of the membrane.

The final electron receptor of complex I, coenzyme Q, is mobile—that is to say, it is free to move in the membrane and to pass the electrons it has gained to the third complex for further transport to oxygen. We shall now see that the second complex also transfers electrons from an oxidizable substrate to coenzyme Q.

Complex II The second of the four membrane-bound complexes,succinate-CoQ oxidoreductase, also catalyzes the transfer of electrons to coenzyme Q.However, its source of electrons (in other words, the substance being oxidized) differs from the oxidizable substrate (NADH) acted on by NADH-CoQ oxidoreductase. In this case the substrate is succinate from the citric acid cycle, which is oxidized to fumarate by a flavin enzyme (see Figure 20.6).

Succinate + E—FAD - > Fumarate + E—FADH2

The notation E—FAD indicates that the flavin portion is covalently bonded to the enzyme. The flavin group is reoxidized in the next stage of the reaction as another iron–sulfur protein is reduced:

E—FADH2 + Fe—Soxidized - > E—FAD + Fe—Sreduced


This reduced iron–sulfur protein then donates its electrons to oxidized coenzyme Q, and coenzyme Q is reduced.

Fe—Sreduced + CoQ + 2H+ - > Fe—Soxidized + CoQH2

The overall reaction is

Succinate + CoQ - > Fumarate + CoQH2

We already saw the first step of this reaction when we discussed the oxidation of succinate to fumarate as part of the citric acid cycle. The enzyme traditionally called succinate dehydrogenase, which catalyzes the oxidation of succinate to fumarate, has been shown by later work to be a part of this enzyme complex. Recall that the succinate dehydrogenase portion consists of a flavoprotein and an iron–sulfur protein. The other components of Complex

are a β-type cytochrome and two iron–sulfur proteins. The whole complex is an integral part of the inner mitochondrial membrane. The standard free-energy change ( ∆G°') is –13.5 kJ mol–1 = –3.2 kcal mol–1. The overall reaction is exergonic, but there is not enough energy from this reaction to drive ATP production, and no hydrogen ions are pumped out of the matrix during this step.

In further steps of the electron transport chain, electrons are passed from coenzyme Q, which is then reoxidized, to the first of a series of very similar pro-teins called cytochromes. Each of these proteins contains a heme group, and in each heme group the iron is successively reduced to Fe(II) and reoxidized to Fe(III). This situation differs from that of the iron in the heme group of hemoglobin, which remains in the reduced form as Fe(II) through the entire process of oxygen transport in the bloodstream. There are also some structural differences between the heme group in hemoglobin and the heme groups in the various types of cytochromes.

The successive oxidation–reduction reactions of the cytochromes

Fe(III) + e 3 Fe(II) (reduction)


Fe(II) 3 Fe(III) + e (oxidation)

differ from one another because the free energy of each reaction, ∆G°, differs from the others because of the influences of the various types of hemes and protein structures. Each of the proteins is slightly different in structure, and thus each protein has slightly different properties, including the tendency to participate in oxidation–reduction reactions. The different types of cytochromes are distinguished by lowercase letters (a, b, c); further distinctions are possible with subscripts, as in c1.

Complex III The third complex, CoQH2- cytochrome c oxidoreductase (alsocalled cytochrome reductase), catalyzes the oxidation of reduced coenzyme Q (CoQH2). The electrons produced by this oxidation reaction are passed along to cytochrome c in a multistep process. The overall reaction is

CoQH2 + 2 Cyt c[Fe(III)] - > CoQ + 2 Cyt c[Fe(II)] + 2H+

Recall that the oxidation of coenzyme Q involves two electrons, whereas the reduction of Fe(III) to Fe(II) requires only one electron. Therefore, two molecules of cytochrome c are required for every molecule of coenzyme Q. The components of this complex include cytochrome b (actually two β-type cytochromes, cytochrome bH and bL), cytochrome c1, and several iron–sulfur proteins (Figure 20.6). Cytochromes can carry electrons, but not hydrogens. This is another location where hydrogen ions leave the matrix. When reduced CoQH2 is oxidized to CoQ, the hydrogen ions pass out on the other side of the membrane.

The third complex is an integral part of the inner mitochondrial mem-brane. Coenzyme Q is soluble in the lipid component of the mitochondrial membrane. It is separated from the complex in the fractionation process that resolves the electron transport apparatus into its component parts, but the coenzyme is probably close to respiratory complexes in the intact membrane (Figure 20.8). Cytochrome c itself is not part of the complex but is loosely bound to the outer surface of the inner mitochondrial membrane, facing the intermembrane space. It is noteworthy that these two important electron carri-ers, coenzyme Q and cytochrome c, are not part of the respiratory complexes but can move freely in the membrane. The respiratory complexes themselves move within the membrane, and electron transport occurs when one complex encounters the next complex in the respiratory chain as they move.

The flow of electrons from reduced coenzyme Q to the other components of the complex does not take a simple, direct path. It is becoming clear that a cyclic flow of electrons involves coenzyme Q twice. This behavior depends on the fact that, as a quinone, coenzyme Q can exist in three forms (Figure 20.9). The semiquinone form, which is intermediate between the oxidized and reduced forms, is of crucial importance here. Because of the crucial involve-ment of coenzyme Q, this portion of the pathway is called the Q cycle.

In part of the Q cycle, one electron is passed from reduced coenzyme Q to the iron–sulfur clusters to cytochrome c1, leaving coenzyme Q in the semiqui-none form.

CoQH2 - > Fe—S - > Cyt c1

The notation Fe—S indicates the iron–sulfur clusters. The series of reactions involving coenzyme Q and cytochrome c1, but omitting the iron–sulfur proteins, can be written as

CoQH2 + Cyt c1(oxidized) - > Cyt c1(reduced) + CoQ (semiquinone anion) + 2H+

The semiquinone, along with the oxidized and reduced forms of coenzyme Q, participates in a cyclic process in which the two b cytochromes are reduced and oxidized in turn. A second molecule of coenzyme Q is involved, transferring a second electron to cytochrome c1, and from there to the mobile carrier cytochrome c. We are going to omit a number of details of the process in the interest of simplicity. Each of the two molecules of coenzyme Q involved in the Q cycle loses one electron. The net result is the same as if one molecule of CoQ had lost two electrons. It is known that one molecule of CoQH2 is regenerated, and one is oxidized to CoQ, which is consistent with this picture. Most important, the Q cycle provides a mechanism for electrons to be transferred one at a time from coenzyme Q to cytochrome c1.

Proton pumping, to which ATP production is coupled, occurs as a result of the reactions of this complex. The Q cycle is implicated in the process, and the whole topic is under active investigation. The standard free-energy change ( ∆G°) is –34.2 kJ = –8.2 kcal for each mole of NADH that enters the electron transport chain (see Figure 20.7). The phosphorylation of ADP requires 30.5 kJ mol1 = 7.3 kcal mol1, and the reaction catalyzed by the third complex supplies enough energy to drive the production of ATP.

Complex IV The fourth complex, cytochrome c oxidase,catalyzes the finalsteps of electron transport, the transfer of electrons from cytochrome c to oxygen.

The overall reaction is

Proton pumping also takes place as a result of this reaction. Like the other respiratory complexes, cytochrome oxidase is an integral part of the inner mitochondrial membrane and contains cytochromes a anda3, as well as two Cu2+ ions that are involved in the electron transport process. Taken as a whole, this complex contains about 10 subunits. In the flow of electrons, the copper ions are intermediate electron acceptors that lie between the two α-type cytochromes in the sequence

Cyt c - > Cyt a - > Cu2+ - > Cyt a3 - > O2

To show the reactions of the cytochromes more explicitly,

Cyt c [reduced, Fe(II)] + Cyt aa3 [oxidized, Fe(III)] - > Cyt aa3 [reduced, Fe(II)] + Cyt c [oxidized, Fe(III)]

Cytochromes a anda3 taken together form the complex known as cytochrome oxidase. The reduced cytochrome oxidase is then oxidized by oxygen, which is itself reduced to water. The half reaction for the reduction of oxygen (oxygen acts as an oxidizing agent) is

Note that in this final reaction we have finally seen the link to molecular oxygen in aerobic metabolism.

The standard free-energy change ( ∆G°') is –110 kJ = –26.3 kcal for each mole of NADH that enters the electron transport chain (see Figure 20.7). We have now seen the three places in the respiratory chain where electron transport is coupled to ATP production by proton pumping. These three places are the NADH dehydrogenase reaction, the oxidation of cytochrome b, and the reac-tion of cytochrome oxidase with oxygen, although the mechanism for proton transfer in cytochrome oxidase remains a mystery. Table 20.2 summarizes the energetics of electron transport reactions.

What is the nature of the iron-containing proteins of electron transport?

In contrast to the electron carriers in the early stages of electron transport, such as NADH, FMN, and CoQ, the cytochromes are macromolecules. These proteins are found in all types of organisms and are typically located in membranes. In eukaryotes, the usual site is the inner mitochondrial membrane, but cytochromes can also occur in the endoplasmic reticulum.

All cytochromes contain the heme group, which is also a part of the struc-ture of hemoglobin and myoglobin. In the cytochromes, the iron of the heme group does not bind to oxygen; instead, the iron is involved in the series of redox reactions, which we have already seen. There are differences in the side chains of the heme group of the cytochromes involved in the various stages of electron transport (Figure 20.10). These structural differences, com-bined with the variations in the polypeptide chain and in the way the polypep-tide chain is attached to the heme, account for the differences in properties among the cytochromes in the electron transport chain.

Nonheme iron proteins do not contain a heme group, as their name indi-cates. Many of the most important proteins in this category contain sulfur, as is the case with the iron–sulfur proteins that are components of the respiratory complexes. The iron is usually bound to cysteine or to S2– (Figure 20.11). There are still many questions about the location and mode of action of iron–sulfur proteins in mitochondria.


The electron transport chain consists of four multisubunit membrane-bound complexes and two mobile electron carriers (coenzyme Q and cytochrome c). The reactions that take place in three of these complexes generate enough energy to drive the phosphorylation of ADP to ATP.

Many proteins of the electron transport chain contain iron, either as part of a heme or combined with sulfur.


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