Gluconeogenesis anabolic reactions

With two exceptions (lysine and leucine see below), all of the proteinogenic amino acids are also glucogenic. Quantitatively, they represent the most important precursors for gluconeogenesis. At the same time, they also have an anaplerotic effect—1. e., they replenish the tricarboxylic acid cycle in order to feed the anabolic reactions that originate in it (see p. 138). 

Figure 7-1. Pathways of fuel metabolism and oxidative phosphorylation. Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis, or for oxidation to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Long-chain fatty acids are transported into mitochondria, where they undergo [ -oxidation to ketone bodies (liver) or to acetyl-CoA (liver and other tissues). Reducing equivalents (NADH, FADII2) are generated by reactions catalyzed by the PDC and the tricarboxylic acid (TCA) cycle and donate electrons (e ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (Complex 0 or at succinate ubiquinone oxidoreductase (Complex ID- Cytochrome c oxidase (Complex IV) catalyzes the reduction of molecular oxygen to water, and ATP synthase (Complex V) generates ATP fromADP Reprinted with permission from Stacpoole et al. (1997).

The solution to this problem is to have an alternative pathway for oxaloacetate synthesis that can produce enough oxaloacetate to supply the anabolic and catabolic requirements of the cell. Although bacteria and plants have several mechanisms, the only way that mammalian cells can produce more oxaloacetate is by the carboxylation of pyruvate, a reaction that is also important in gluconeogenesis. This reaction is... 

The anabolic reactions of gluconeogenesis take place in the cytosol. Oxaloacetate is not transported across the mitochondrial membrane. Two mechanisms exist for the transfer of molecules needed for gluconeogenesis from mitochondria to the cytosol. One mechanism takes advantage of the fact that phosphoenolpyruvate can be formed from oxaloacetate in the mitochondrial matrix (this reaction is the next step in gluconeogenesis) phosphoenolpyruvate is then transferred to the cytosol, where the remaining reactions take place (Figure 19.12). The other mechanism relies on the fact that malate, which is another intermediate of the citric acid cycle, can be transferred to the cytosol. There is a malate dehydrogenase enzyme in the cytosol as well as in mitochondria, and malate can be converted to oxaloacetate in the cytosol. 

While the citric acid cycle takes place in mitochondria, many anabolic reactions take place in the cytosol. Oxaloacetate, the starting material for gluconeogenesis, is a component of the citric acid cycle. Malate, but not oxaloacetate, can be transported across the mitochondrial membrane. After malate from mitochondria is carried to the cytosol, it can be converted to oxaloacetate by malate dehydrogenase, an enzyme that requires NAD+. Malate, which crosses the mitochondrial membrane, plays a role in lipid anabolism, in a reaction in which malate is oxidatively decarboxylated to pyruvate by an enzyme that requires NADP+, producing NADPH. 

The anabolism of fatty acids is not simply a reversal of the reactions of P-oxidation. Anabolism and catabolism are not, in general, the exact reverse of each other for instance, gluconeogenesis (Section 18.2) is not simply a reversal of the reactions of glycolysis. A hrst example of the differences between the degradation and the biosynthesis of fatty acids is that the anabolic reactions take place in the cytosol. We have just seen that the degradative reactions of P-oxidation take place in the mitochondrial matrix. The first step in fatty-acid biosynthesis is transport of acetyl-GoA to the cytosol. 

The intermediates of the tricarboxylic acid cycle are present in the mitochondria only in very small quantities. After the oxidation of acetyl-CoA to CO2, they are constantly regenerated, and their concentrations therefore remain constant, averaged over time. Anabolic pathways, which remove intermediates of the cycle (e.g., gluconeogenesis) would quickly use up the small quantities present in the mitochondria if metabolites did not reenter the cycle at other sites to replace the compounds consumed. Processes that replenish the cycle in this way are called anaplerotic reactions. 

This reaction, which produces oxaloacetate from pyruvate, provides a connection between the amphibolic citric acid cycle and the anabolism of sugars by gluconeogenesis. On this same topic of carbohydrate anabolism, we should note again that pyruvate cannot be produced from acetyl-GoA in mammals. Because acetyl-GoA is the end product of catabolism of latty acids, we can see that mammals could not exist with fats or acetate as the sole carbon source. The intermediates of carbohydrate metabolism would soon be depleted. Garbohydrates are the principal energy and carbon source in animals (Figure 19.11), and glucose is especially critical in humans because it is the preferred fuel for our brain cells. Plants can carry out the conversion of acetyl-GoA to pyruvate and oxaloacetate, so they can exist without carbohydrates as a carbon source. The conversion of pyruvate to acetyl-GoA does take place in both plants and animals (see Section 19.3). 

The one-carbon unit transferred in this reaction is bound to tetrahydrofolate, forming A ,A/ °-methylenetetrahydrofolate, in which the methylene (one-carbon) unit is bound to two of the nitrogens of the carrier (Figure 23.12). Tetrahydrofolate is not the only carrier of one-carbon units. We have already encountered biotin, a carrier of GOg, and we have discussed the role that biotin plays in gluconeogenesis (Section 18.2) and in the anabolism of fatty acids (Section 21.6). 

Goenzymes are introduced in this chapter and are discussed in later chapters in the context of the reactions in which they play a role. Chapter 16 discusses carbohydrates. Chapter 17 begins the overview of the metabohc pathways by discussing glycolysis. Glycogen metabolism, gluconeogenesis, and the pentose phosphate pathway (Chapter 18) provide bases for treating control mechanisms in carbohydrate metabolism. Discussion of the citric acid cycle is followed by the electron transport chain and oxidative phosphorylation in Chapters 19 and 20. The catabolic and anabolic aspects of lipid metabohsm are dealt with in Chapter 21. In Chapter 22, photosynthesis rounds out the discussion of carbohydrate metabolism. Chapter... 

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