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You learned in Chapter 16 that glucose can be metabolized in glycolysis to pyruvate, yielding some ATP. However, the process of glycolysis is inefficient, capturing only a fraction of the energy inherent in a glucose molecule as ATP. More of the energy can be accessed if the pyruvate is completely oxidized into carbon dioxide and water. The combustion of fuels into carbon dioxide and water to generate ATP is called cellular respiration and is the source of more than 90% of the ATP required by human beings. Cellular respiration, unlike glycolysis, is an aerobic process, requiring molecular oxygen—O₂. In eukaryotes, cellular respiration takes place inside the double-membrane-bounded mitochondria, whereas glycolysis is cytoplasmic.

Cellular respiration can be divided into two parts. First, carbon fuels are completely oxidized with a concomitant generation of high-transfer-potential electrons in a series of reactions variously called the citric acid cycle (CAC), the tricarboxylic acid (TCA) cycle, or the Krebs cycle, after Sir Hans Krebs, the first to propose the existence of the cycle. In the second part of cellular respiration, referred to as oxidative phosphorylation, the high-transfer-potential electrons are transferred to oxygen to form water in a series of oxidation–reduction reactions. This transfer is highly exergonic, and the released energy is used to synthesize ATP. We will focus on the citric acid cycle in this section, leaving oxidative phosphorylation until Section 10.

The citric acid cycle is the central metabolic hub of the cell. It is the gateway to the aerobic metabolism of all fuel molecules. The cycle is also crucial for anabolism, serving as an important source of precursors for the building blocks of many other molecules such as amino acids, nucleotide bases, and porphyrin (the organic component of heme). The citric acid cycle component oxaloacetate also is an important precursor to glucose.

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We begin this section by examining a crucial reaction in living systems: the conversion of glucose-derived pyruvate into acetyl CoA, an activated acetyl unit and the actual substrate for the citric acid cycle. This reaction links glycolysis and cellular respiration, thus allowing for the complete combustion of glucose, a fundamental fuel in all living systems. We will then study the citric acid cycle itself, the final common pathway for the oxidation of all fuel molecules, carbohydrates, fats, and amino acids.

✓ By the end of this section, you should be able to: