O

to FAD, yielding the reduced form of this coenzyme, FADH2. In reaction 6, hydrolysis of the high-energy thioester bond in succinyl CoA is coupled to synthesis of one GTP by substratelevel phosphorylation (GTP and ATP are interconvertible). Reaction 9, the final one, also regenerates oxaloacetate, so the cycle can begin again. Note that molecular O2 does not participate in the citric acid cycle.

Most enzymes and small molecules involved in the citric acid cycle are soluble in aqueous solution and are localized to the mitochondrial matrix. These include CoA, acetyl CoA, succinyl CoA, NAD+, and NADH, as well as six of the eight cycle enzymes. Succinate dehydrogenase, (reaction 7) and a-ketoglu-tarate dehydrogenase (reaction 5) are integral proteins in the inner membrane, with their active sites facing the matrix. When mitochondria are disrupted by gentle ultrasonic vibration or osmotic lysis, the six non-membrane-bound enzymes in the citric acid cycle are released as a very large multiprotein complex. The reaction product of one enzyme is thought to pass directly to the next enzyme without diffusing through the solution. However, much work is needed to determine the structure of this enzyme complex as it exists in the cell.

Since glycolysis of one glucose molecule generates two acetyl CoA molecules, the reactions in the glycolytic pathway and citric acid cycle produce six CO2 molecules, ten NADH molecules, and two FADH2 molecules per glucose molecule (Table 8-1). Although these reactions also generate four high-energy phosphoanhydride bonds in the form of two ATP and two GTP molecules, this represents only a small fraction of the available energy released in the complete aerobic oxidation of glucose. The remaining energy is stored in the reduced coenzymes NADH and FADH2.

Synthesis of most of the ATP generated in aerobic oxidation is coupled to the reoxidation of NADH and FADH2 by O2 in a stepwise process involving the respiratory chain, also called the electron transport chain. Even though molecular O2 is not involved in any reaction of the citric acid cycle, in the absence of O2 the cycle soon stops operating as the supply of NAD+ and FAD dwindles. Before considering electron transport and the coupled formation of ATP in detail, we discuss first how the supply of NAD+ in the cytosol is regenerated and then the oxidation of fatty acids to CO2.

TABLE 8-1 Net Result of the Glycolytic Pathway and the Citric Acid Cycle

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