Chapter 16 The Citric Acid Cycle in Part II Bioenergetics and Metabolism

Chapter 16 The Citric Acid Cycle

An illustration depicts the chapter opener

As we saw in Chapter 14, some cells obtain energy (ATP) by fermentation, breaking down glucose in the absence of oxygen. For most eukaryotic cells and many bacteria, which live under aerobic conditions and oxidize their organic fuels to carbon dioxide and water, glycolysis is but the first stage in the complete oxidation of glucose. Rather than being reduced to lactate, ethanol, or some other fermentation product, the pyruvate produced by glycolysis is further oxidized to $H_{2} O$ $upper H Subscript 2 Baseline upper O$ and ${CO}_{2}$ $CO Subscript 2$ through the process of cellular respiration.

Cellular respiration occurs in three major stages (Fig. 16-1), the first two of which we discuss in this chapter. In the first, organic fuel molecules — glucose, fatty acids, and some amino acids — are oxidized to yield two-carbon fragments in the form of the acetyl group of acetyl-coenzyme A (acetyl-CoA). In the second stage, the acetyl groups are oxidized to ${CO}_{2}$ $CO Subscript 2$ in the citric acid cycle, also called the tricarboxylic acid (TCA) cycle or the Krebs cycle (after its discoverer, Hans Krebs). Much of the energy of these oxidations is conserved in the reduced electron carriers NADH and ${FADH}_{2}$ $FADH Subscript 2$ . In the third stage of respiration, these reduced coenzymes are themselves oxidized, giving up protons $(H^{+})$ $left-parenthesis upper H Superscript plus Baseline right-parenthesis$ and electrons. The electrons are transferred to $O_{2}$ $upper O Subscript 2$ via a series of electron-carrying molecules known as the respiratory chain, resulting in the formation of water. In the course of electron transfer, much of the energy available from redox reactions is conserved in the form of ATP, by a process called oxidative phosphorylation. We discuss this third stage in Chapter 19.

A figure shows how proteins, fats, and carbohydrates are catabolized in three stages of cellular respiration: acetyl-Co A production, acetyl Co-A oxidation, and electron transfer and oxidative phosphorylation. — FIGURE 16-1 Catabolism of proteins, fats, and carbohydrates in the three stages of cellular respiration. Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl-CoA. Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by NADH and ${FADH}_{2}$ $FADH Subscript 2$ are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane–bound) electron carriers — the respiratory chain — ultimately reducing $O_{2}$ $upper O Subscript 2$ to $upper H Subscript 2 Baseline upper O$ $upper H Subscript 2 Baseline upper O$ . This electron flow drives the production of ATP.

FIGURE 16-1 Catabolism of proteins, fats, and carbohydrates in the three stages of cellular respiration. Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl-CoA. Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by NADH and ${FADH}_{2}$ $FADH Subscript 2$ are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane–bound) electron carriers — the respiratory chain — ultimately reducing $O_{2}$ $upper O Subscript 2$ to $upper H Subscript 2 Baseline upper O$ $upper H Subscript 2 Baseline upper O$ . This electron flow drives the production of ATP.

The figure is divided into three horizontal pieces. The top piece is labeled stage 1: Acetyl-Co A production. The middle stage is labeled stage 2: Acetyl Co A oxidation. The bottom stage is labeled Stage 3: Electron transfer and oxidative phosphorylation. At the top, in stage 1, amino acids, fatty acids, and glucose are shown across the top, each with a blue arrow pointing downward. Amino acids has a blue arrow that points down and gives off a red arrow labeled e minus that continues down to a yellow box labeled N A D H, F A D H 2 (reduced e minus carriers) across the line dividing the bottom of stage 2 from the top of stage 3. The blue arrow from amino acids then curves right to the top left of a yellow box labeled acetyl Co A that extends from the bottom of stage 1 to the top of stage 2. Fatty acids has a similar blue line that extends down, gives off a red arrow labeled e-minus that points left and then joins the red arrow from the blue arrow from amino acids to point down to the yellow box labeled N A D H, F A D H 2 (reduced e minus carriers). The blue arrow from fatty acids then bends right to enter the upper right side of the box labeled acetyl C o A. Glucose has a blue downward arrow that points down to pyruvate and is next to a blue box labeled glycolysis. A red arrow labeled e minus extends to the left and passes through the red arrow from the blue arrow from fatty acids to join with it. A second blue arrow points down from pyruvate to the yellow box labeled acetyl C o A. A red arrow labeled e -minus branches off and joins with the red arrow from e minus from glycolysis before both join with the e-minus from fatty acids. A blue arrow to C O 2 branches off from the blue arrow from pyruvate to acetyl Co A. In stage 2, a blue arrow points down from acetyl Co A to the twelve o’clock position of a circle of blue arrows labeled citric acid cycle and curves to the right, ending at citrate at the one o’clock position. Another blue arrow points down from citrate until a piece curves off to show the release of C O 2 at the five o’clock position. At the start of the arrow that continues clockwise from the five o’clock position, a red arrow branches off to point to e minus and then continues to the yellow box labeled N A D H, F A D H 2 (reduced e minus carriers). The blue arrow continues clockwise to just past the six o’clock position, where it branches off to show the loss of C O 2. A clockwise blue arrow continues from this point to oxaloacetate at the eleven o’clock position. Three red arrows branch off along this piece of clockwise arrow to point to e-minus. The top two join with the arrow down from e-minus from stage 1 and all end at the yellow box labeled N A D H, F A D H 2 (reduced e minus carriers). The bottom one points directly to the yellow box labeled N A D H, F A D H 2 (reduced e minus carriers). In stage 3, a red arrow labeled e minus points down from the yellow box labeled N A D H, F A D H 2 (reduced e minus carriers) to a blue box below labeled respiratory (electron-transfer) chain. A blue curved arrow against the right side of the blue box shows that 2 H plus plus one half O 2 are added and H 2 O leaves. A curved blue arrow across the bottom of the blue box shows that A D P plus P I is added and A T P leaves. All data are approximate.

A photo shows Hans Krebs wearing a white lab coat and holding a piece of equipment in front of a bench covered with shelving and equipment. — Hans Krebs, 1900–1981

We use these principles as our guide to this chapter:

Pyruvate is the metabolite that links two central catabolic pathways, glycolysis and the citric acid cycle. It is therefore a logical point for regulation that determines the rate of catabolic activity and the partitioning of pyruvate among its possible uses.
The reactions of the citric acid cycle follow a chemical logic. In its catabolic role the citric acid cycle oxidizes acetyl-CoA to ${CO}_{2}$ $CO Subscript 2$ and $H_{2} O$ $upper H Subscript 2 Baseline upper O$ . Energy from the oxidations in the cycle drives the synthesis of ATP. The chemical strategies for activating groups for oxidation and for conserving energy in the form of reducing power and high-energy compounds are used in many other biochemical pathways.
The citric acid cycle is a hub of metabolism, with catabolic pathways leading in and anabolic pathways leading out. Acetate groups (acetyl-CoA) from the catabolism of various fuels are used in the synthesis of such metabolites as amino acids, fatty acids, and sterols. The breakdown products of many amino acids and nucleotides are intermediates of the cycle, and they can be fed in or siphoned off as needed by the cell.
The central role of the citric acid cycle in metabolism requires that it be regulated in coordination with many other pathways. Regulation occurs by both allosteric and covalent mechanisms that overlap and interact to achieve homeostasis. Some mutations that affect the reactions of the citric acid cycle lead to tumor formation.
Enzymes have evolved to form complexes to efficiently achieve a series of chemical transformations without releasing the intermediates into the bulk solvent. This strategy, seen in the pyruvate dehydrogenase complex and the metabolons of the citric acid cycle, is ubiquitous in other pathways of metabolism, in respiration, and in the many “ — somes” that assemble and disassemble informational macromolecules.