Reactions of the Citric Acid Cycle: -Anaplerotic Reactions Replenish Citric Acid Cycle Intermediates
As intermediates of the citric acid cycle are removed to serve as biosynthetic precursors, they are replenished by Anaplerotic reactions (Fig. 16–15; Table 16–2). Under normal circumstances, the reactions by which cycle intermediates are siphoned off into other pathways and those by which they are replenished are in dynamic balance, so that the concentrations of the citric acid cycle intermediates remain almost constant.
FIGURE 16–15 Role of the citric acid cycle in anabolism. Intermediates of the citric acid cycle are drawn off as precursors in many biosynthetic pathways. Shown in red are four anaplerotic reactions that replenish depleted cycle intermediates (see Table 16–2).
Table 16–2 shows the most common anaplerotic re actions, all of which, in various tissues and organisms, convert either pyruvate or phosphoenolpyruvate to oxaloacetate or malate. The most important anaplerotic re action in mammalian liver and kidney is the reversible carboxylation of pyruvate by CO2 to form oxaloacetate, catalyzed by pyruvate carboxylase. When the citric acid cycle is deficient in oxaloacetate or any other intermediates, pyruvate is carboxylated to produce more oxaloacetate. The enzymatic addition of a carboxyl group to pyruvate requires energy, which is supplied by ATP—the free energy required to attach a carboxyl group to pyruvate is about equal to the free energy available from ATP. Pyruvate carboxylase is a regulatory enzyme and is virtually inactive in the absence of acetyl-CoA, its positive allosteric modulator. Whenever acetyl-CoA, the fuel for the citric acid cycle, is present in excess, it stimulates the pyruvate carboxylase reaction to produce more oxaloacetate, enabling the cycle to use more acetyl-CoA in the citrate synthase reaction. The other anaplerotic reactions shown in Table 16–2 are also regulated to keep the level of intermediates high enough to support the activity of the citric acid cycle. Phosphoenolpyruvate (PEP) carboxylase, for example, is activated by the glycolytic intermediate fructose 1,6 bisphosphate, which accumulates when the citric acid cycle operates too slowly to process the pyruvate generated by glycolysis.
