Chapter 17: The Citric Acid Cycle

A detailed examination of the cycle's eight enzymatic steps follows, describing how citrate synthase condenses acetyl CoA and oxaloacetate to form citrate, which is then processed by aconitase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase to release carbon dioxide and generate high-energy electrons stored in NADH. The text explains how succinyl CoA synthetase performs the cycle's only substrate-level phosphorylation to yield ATP or GTP, while succinate dehydrogenase—embedded in the inner mitochondrial membrane—produces FADH2, followed by the actions of fumarase and malate dehydrogenase to regenerate oxaloacetate. Regulation is a primary focus, detailing how the PDH complex is controlled via reversible phosphorylation and allosteric effectors like ATP, ADP, and NADH, and how the cycle itself is regulated at the isocitrate and alpha-ketoglutarate dehydrogenase steps based on the cell's energy charge. The summary also explores the cycle's amphibolic nature, serving as a source of biosynthetic precursors for amino acids and heme, and the necessity of anaplerotic reactions like pyruvate carboxylase to replenish intermediates. Clinical correlations are highlighted, including the neurological effects of beriberi (thiamine deficiency) and arsenic poisoning, as well as the metabolic shifts in cancer cells involving hypoxia-inducible factor 1 (HIF-1) and oncometabolites. Finally, the chapter contrasts mammalian metabolism with the glyoxylate cycle in plants and bacteria, which employs isocitrate lyase and malate synthase to bypass decarboxylation and enable the net conversion of fatty acids into glucose.