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OBJECTIVES
After studying this chapter, you should be able to:
Describe the reactions of the citric acid cycle and the reactions that lead to the production of reducing equivalents that are oxidized in the mitochondrial electron transport chain to yield ATP.
Explain the importance of vitamins in the citric acid cycle.
Explain how the citric acid cycle provides both a route for catabolism of amino acids and also a route for their synthesis.
Describe the main anaplerotic pathways that permit replenishment of citric acid cycle intermediates, and how the withdrawal of oxaloacetate for gluconeogenesis is controlled.
Describe the role of the citric acid cycle in fatty acid synthesis.
Explain how the activity of the citric acid cycle is controlled by the availability of oxidized cofactors.
Explain how hyperammonemia can lead to loss of consciousness.
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BIOMEDICAL IMPORTANCE
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The citric acid cycle (the Krebs or tricarboxylic acid cycle) is a sequence of reactions in mitochondria that oxidizes the acetyl moiety of acetyl-CoA to CO2 and reduces coenzymes that are reoxidized through the electron transport chain (see Chapter 13), linked to the formation of ATP.
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The citric acid cycle is the final common pathway for the oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but liver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). The few genetic defects of citric acid cycle enzymes that have been reported are associated with severe neurological damage as a result of very considerably impaired ATP formation in the central nervous system.
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Hyperammonemia, as occurs in advanced liver disease, leads to loss of consciousness, coma, and convulsions as a result of impaired activity of the citric acid cycle, leading to reduced formation of ATP. Ammonia both depletes citric acid cycle intermediates (by withdrawing α-ketoglutarate for the formation of glutamate and glutamine) and also inhibits the oxidative decarboxylation of α-ketoglutarate.
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THE CITRIC ACID CYCLE PROVIDES SUBSTRATES FOR THE RESPIRATORY CHAIN
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The cycle starts with reaction between the acetyl moiety of acetyl-CoA and the four-carbon dicarboxylic acid oxaloacetate, forming a six-carbon tricarboxylic acid, citrate. In the subsequent reactions, two molecules of CO2 are released and oxaloacetate is regenerated (Figure 16–1). Only a small quantity of oxaloacetate is needed for the oxidation of a large quantity of acetyl-CoA; it can be considered as playing a catalytic role, since it is regenerated at the end of the cycle.
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