Figure 422

The Krebs-cycle pathway. Note that the carbon atoms in the two molecules of CO2 produced by a turn of the cycle are not the same two carbon atoms that entered the cycle as an acetyl group (identified by the dashed boxes in this figure).

Now we come to a crucial fact: In addition to producing carbon dioxide, intermediates in the Krebs cycle generate hydrogen atoms, most of which are transferred to the coenzymes NAD+ and FAD to form NADH and FADH2. This hydrogen transfer to NAD+ occurs in each of steps 3, 4, and 8, and to FAD in reaction 6. These hydrogens will be transferred from the coenzymes, along with the free H+, to oxygen in the next stage of fuel metabolism—oxidative phosphorylation. Since oxidative phosphorylation is necessary for regeneration of the hydrogen-free form of these coen-zymes, the Krebs cycle can operate only under aerobic conditions. There is no pathway in the mitochondria that can remove the hydrogen from these coenzymes under anaerobic conditions.

So far we have said nothing of how the Krebs cycle contributes to the formation of ATP. In fact, the Krebs cycle directly produces only one high-energy nu-cleotide triphosphate. This occurs during reaction 5 in which inorganic phosphate is transferred to guanosine

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

Protein Activity and Cellular Metabolism CHAPTER FOUR

Protein Activity and Cellular Metabolism CHAPTER FOUR

TABLE 4-6 Characteristics of the Krebs Cycle

Entering substrate

Acetyl coenzyme A—acetyl groups derived from pyruvate, fatty acids, and amino acids Some intermediates derived from amino acids

Enzyme location

Inner compartment of mitochondria (the mitochondrial matrix)

ATP production

1 GTP formed directly, which can be converted into ATP

Operates only under aerobic conditions even though molecular oxygen is not used directly in this pathway

Coenzyme production

3 NADH + 3 H+ and 2 FADH2

Final products

2 CO2 for each molecule of acetyl coenzyme A entering pathway

Some intermediates used to synthesize amino acids and other organic molecules required for special cell functions

Net reaction

2 CO2 + CoA + 3 NADH + 3 H+ + FADH2 + GTP

diphosphate (GDP) to form guanosine triphosphate (GTP). The hydrolysis of GTP, like that of ATP, can provide energy for some energy-requiring reactions. In addition, the energy in GTP can be transferred to ATP by the reaction

This reaction is reversible, and the energy in ATP can be used to form GTP from GDP when additional GTP is required for protein synthesis (Chapter 5) and signal transduction (Chapter 7).

To reiterate, the formation of ATP from GTP is the only mechanism by which ATP is formed within the Krebs cycle. Why, then, is the Krebs cycle so important? Because the hydrogen atoms transferred to coenzymes during the cycle (plus the free hydrogen ions generated) are used in the next pathway, oxidative phosphorylation, to form large amounts of ATP.

The net result of the catabolism of one acetyl group from acetyl CoA by way of the Krebs cycle can be written:

One more point should be noted: Although the major function of the Krebs cycle is to provide hydrogen atoms to the oxidative-phosphorylation pathway, some of the intermediates in the cycle can be used to synthesize organic molecules, especially several types of amino acids, required by cells. Oxaloacetate is one of the intermediates used in this manner. When a molecule of oxaloacetate is removed from the Krebs cycle in the process of forming amino acids, however, it is not available to combine with the acetate fragment of acetyl CoA at the beginning of the cycle. Thus, there must be a way of replacing the oxaloacetate and other Krebs-cycle intermediates that are consumed in syn thetic pathways. Carbohydrates provide one source of oxaloacetate replacement by the following reaction, which converts pyruvate into oxaloacetate.

Certain amino acid derivatives, as we shall see, can also be used to form oxaloacetate and other Krebs-cycle intermediates.

Table 4-6 summarizes the characteristics of the Krebs cycle reactions.

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