Oxidative Phosphorylation

Oxidative phosphorylation provides the third, and quantitatively most important, mechanism by which energy derived from fuel molecules can be transferred to ATP. The basic principle behind this pathway is simple: The energy transferred to ATP is derived from the energy released when hydrogen ions combine with molecular oxygen to form water. The hydrogen comes from the NADH + H+ and FADH2 coenzymes generated by the Krebs cycle, by the metabolism of fatty acids (see below), and, to a much lesser extent, during aerobic glycolysis. The net reaction is

The proteins that mediate oxidative phosphorylation are embedded in the inner mitochondrial membrane unlike the enzymes of the Krebs cycle, which are soluble enzymes in the mitochondrial matrix. The proteins for oxidative phosphorylation can be divided into two groups: (1) those that mediate the series of reactions by which hydrogen ions are transferred to molecular oxygen, and (2) those that couple the energy released by these reactions to the synthesis of ATP.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART ONE Basic Cell Functions

Most of the first group of proteins contain iron and copper cofactors, and are known as cytochromes (because in pure form they are brightly colored). Their structure resembles the red iron-containing hemoglobin molecule, which binds oxygen in red blood cells. The cytochromes form the components of the electron transport chain, in which two electrons from the hydrogen atoms are initially transferred either from NADH + H+ or FADH2 to one of the elements in this chain. These electrons are then successively transferred to other compounds in the chain, often to or from an iron or copper ion, until the electrons are finally transferred to molecular oxygen, which then combines with hydrogen ions (protons) to form water. These hydrogen ions, like the electrons, come from the free hydrogen ions and the hydrogen-bearing co-enzymes, having been released from them early in the transport chain when the electrons from the hydrogen atoms were transferred to the cytochromes.

Importantly, in addition to transferring the coen-zyme hydrogens to water, this process regenerates the hydrogen-free form of the coenzymes, which then become available to accept two more hydrogens from intermediates in the Krebs cycle, glycolysis, or fatty acid pathway (as described below). Thus, the electron transport chain provides the aerobic mechanism for regenerating the hydrogen-free form of the coenzymes, whereas, as described earlier, the anaerobic mechanism, which applies only to glycolysis, is coupled to the formation of lactate.

At each step along the electron transport chain, small amounts of energy are released, which in total account for the full 53 kcal/mol released from a direct reaction between hydrogen and oxygen. Because this energy is released in small steps, it can be linked to the synthesis of several molecules of ATP, each of which requires only 7 kcal/mol.

ATP is formed at three points along the electron transport chain. The mechanism by which this occurs is known as the chemiosmotic hypothesis. As electrons are transferred from one cytochrome to another along the electron transport chain, the energy released is used to move hydrogen ions (protons) from the matrix into the compartment between the inner and outer mitochondrial membranes (Figure 4-23), thus producing a source of potential energy in the form of a hydrogen-ion gradient across the membrane. At three points along the chain, a protein complex forms a channel in the inner mitochondrial membrane through which the hydrogen ions can flow back to the matrix side and in the process transfer energy to the formation of ATP from ADP and Pi. FADH2 has a slightly lower chemical energy content than does NADH + H+ and enters the electron transport chain at a point

Inner mitochondrial Outer mitochondrial membrane membrane

Inner mitochondrial Outer mitochondrial membrane membrane

Fadh2 Reactive Site

Cytochromes in electron transport chain

FIGURE 4-23

ATP is formed during oxidative phosphorylation by the flow of hydrogen ions across the inner mitochondrial membrane. Two or three molecules of ATP are produced per pair of electrons donated, depending on the point at which a particular coenzyme enters the electron transport chain. fôï EWfl

Cytochromes in electron transport chain

FIGURE 4-23

ATP is formed during oxidative phosphorylation by the flow of hydrogen ions across the inner mitochondrial membrane. Two or three molecules of ATP are produced per pair of electrons donated, depending on the point at which a particular coenzyme enters the electron transport chain. fôï EWfl

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

I. Basic Cell Functions

4. Protein Activity and Cellular Metabolism

© The McGraw-Hill Companies, 2001

Protein Activity and Cellular Metabolism CHAPTER FOUR

Protein Activity and Cellular Metabolism CHAPTER FOUR

TABLE 4-7 Characteristics of Oxidative Phosphorylation

Entering substrates

Hydrogen atoms obtained from NADH + H+ and FADH2 formed (1) during glycolysis,

(2) by the Krebs cycle during the breakdown of pyruvate and amino acids, and

(3) during the breakdown of fatty acids Molecular oxygen

Enzyme location

Inner mitochondrial membrane

ATP production

3 ATP formed from each NADH + H + 2 ATP formed from each FADH2

Final products

H2O—one molecule for each pair of hydrogens entering pathway.

Net reaction

1 O2 + NADH + H+ + 3 ADP + 3 P. -> H2O + NAD+ + 3 ATP

beyond the first site of ATP generation (Figure 4-23). Thus, the transfer of its electrons to oxygen produces only two ATP rather than the three formed from NADH + H+.

To repeat, the majority of the ATP formed in the body is produced during oxidative phosphorylation as a result of processing hydrogen atoms that originated largely from the Krebs cycle, during the breakdown of carbohydrates, fats, and proteins. The mitochondria, where the oxidative phosphorylation and the Krebs-cycle reactions occur, are thus considered the powerhouses of the cell. In addition, as we have just seen, it is within these organelles that the majority of the oxygen we breathe is consumed, and the majority of the carbon dioxide we expire is produced.

Table 4-7 summaries the key features of oxidative phosphorylation.

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