Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Metabolism of Carbohydrates and Lipids
The Citric Acid Cycle: Catabolism of Acetyl-CoA
Amphibolic Role of the Citric Acid Cycle

Some metabolic pathways terminate with metabolites that are part of the cycle, whereas others originate from its metabolites. These include Gluconeogenesis, Transamination, deamination, and fatty acid synthesis. These processes are discussed in greater detail in subsequent chapters; their relationship with the cycle reactions is briefly outlined below.

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Fig. 17.6. Synthesis of coenzyme A from pantothenic acid.

Gluconeogenesis, Transamination, and Deamination

All major intermediates participating in the cycle, from citrate to oxaloacetate, are potentially glucogenic. Glucose can be synthesized from them in both The Liver and Kidneys, as these Organs contain the complete set of Enzymes required for gluconeogenesis (see p. 196). The key enzyme in gluconeogenesis is phosphoenolpyruvate carboxykinase, which catalyzes the decarboxylation of oxaloacetate (using GTP as a high-energy phosphate source) to yield phosphoenolpyruvate (Fig. 17.7):

Oxaloacetate + GTP → Phosphoenolpyruvate + СО₂ + GDP.

Intermediates enter the cycle via several different reactions. One of The most significant is The formation of oxaloacetate through the carboxylation of Pyruvate, catalyzed by pyruvate carboxylase:

АТР + СО₂ + Н₂О + pyruvate → oxaloacetate + ADP + Р_i.

This reaction maintains adequate concentrations of oxaloacetate for its Condensation with acetyl-CoA. When acetyl-CoA levels rise, it acts as an allosteric activator of pyruvate carboxylase, accelerating oxaloacetate production. Lactate, an important substrate for gluconeogenesis, enters the cycle after being converted first into pyruvate and subsequently into oxaloacetate.

In transaminase-catalyzed reactions, pyruvate is formed from Alanine, oxaloacetate from aspartate, and α-ketoglutarate from glutamate. Because these reactions are reversible, the cycle can serve as a source of carbon skeletons for the synthesis of non-Essential Amino Acids. For example:

Other Amino Acids also contribute to gluconeogenesis because, following deamination or transamination, their carbon skeletons are fully or partially integrated into the cycle. Examples include alanine, Cysteine, Glycine, hydroxyproline, Serine, Threonine, and Tryptophan, which yield pyruvate; Arginine, Histidine, glutamine, and Proline, which yield glutamate and subsequently α-ketoglutarate; isoleucine, Methionine, and valine, which yield succinyl-CoA; and Tyrosine and phenylalanine, which yield fumarate (Fig. 17.7). Substances that form pyruvate are either completely oxidized to СО₂ via the pyruvate dehydrogenase pathway leading to acetyl-CoA formation, or channeled into gluconeogenesis to form oxaloacetate via carboxylation.

Fig. 17.7. Participation of The Citric Acid Cycle in transamination and gluconeogenesis. The main pathway of gluconeogenesis is indicated by bold arrows.

Fig. 17.8. Participation of The Citric Acid cycle in the synthesis of Fatty acids from glucose. See also Fig. 23.9.

For ruminants, The conversion of propionate (the primary glucogenic product of rumen Fermentation) into succinyl-CoA via methylmalonyl-CoA is of particular importance (see Fig. 20.2).

Fatty Acid Synthesis (Fig. 17.8)

Acetyl-CoA, produced from pyruvate by the action of pyruvate dehydrogenase, serves as the primary building block for long-chain fatty acid synthesis in mammals (with the exception of ruminants, in which acetyl-CoA is derived directly from acetate). Because pyruvate dehydrogenase is a mitochondrial enzyme, whereas the enzymes for fatty acid synthesis are located extra-mitochondrially, Cells must transport acetyl-CoA across the impermeable mitochondrial membrane. This "transport" is achieved as follows: acetyl-CoA enters the citric acid cycle and is incorporated into citrate; citrate is then transported out of the mitochondrion into the Cytosol, where it is cleaved back into acetyl-CoA in a reaction catalyzed by ATP-citrate lyase.

Citrate + АТР + CoA → Acetyl-CoA + Oxaloacetate + ADP + Р_i.

Regulation of the Citric Acid Cycle

This topic is discussed in Chapter 22.

References

Boyer Р. D. (ed.) The Enzymes, 3rd ed., Academic Press, 1971. Goodwin T. W. (ed.) The Metabolic Roles of Citrate, Academic Press, 1968.

Greville G. D. Vol. 1, p. 297. In: Carbohydrate METABOLISM and

Its Disorders, Dickens F., Randle P. J., Whelan W. J. (eds), Academic Press, 1968.

Lowenstein J.M. Vol. 1, p. 146. In: Metabolic Pathways, 3rd ed., Grenberg D. M. (ed.), Academic Press, 1967.

Lowenstein J. M. (ed.) Citric Acid Cycle: Control and Compartmentation, Dekker, 1969.

Lowenstein J. M. (ed.) Citric Acid Cycle, Vol. 13. In: Methods in Enzymology. Academic Press, 1969.

Srere P. A. The enzymology of the formation and breakdown of citrate, Adv. Enzymol., 1975, 43, 57.