Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
The Citric Acid Cycle
The conversion of pyruvate to acetyl-CoA is regulated

From Chapter 15, we know that The rate of Glycolysis is regulated at two levels. First and foremost, as we have seen, is the Regulation of the supply of 'fuel' for glycolysis itself. Two regulatory Enzymes control The entry of glucose into The Glycolytic Pathway: hexokinase, which catalyzes the phosphorylation of D-glucose to yield glucose-6-phosphate, and Glycogen phosphorylase, which catalyzes the initial step in forming glucose-6-phosphate from glycogen. Similarly, the rate of The Citric Acid Cycle is regulated primarily by controlling the rate at which its 'fuel' is produced. This fuel is acetyl-CoA, which is generated by the Oxidation of Pyruvate and Fatty acids (Chapter 18). Figure 16-14 illustrates how the reaction producing acetyl-CoA, catalyzed by the pyruvate dehydrogenase complex, is regulated in animal Tissues via Covalent Modification of the complex (Section 9.22). When the mitochondrial ATP concentration is relatively high, and when acetyl-CoA and Krebs cycle intermediates are present in sufficient quantities to meet The Cell's energy demands, further production of acetyl-CoA is halted. Under these signaling conditions, ATP acts as a positive modulator that activates an auxiliary enzyme, pyruvate dehydrogenase kinase. This enzyme utilizes ATP to phosphorylate a specific Serine residue in the Active Site of the pyruvate dehydrogenase molecule, converting it into an inactive phosphorylated form, phosphopyruvate dehydrogenase (Figure 16-14). Conversely, if energy demand rises and the ATP level drops accordingly, the inactive, phosphorylated form of pyruvate dehydrogenase can be reactivated. This occurs through the hydrolytic Cleavage of the inhibitory phosphate group from the pyruvate dehydrogenase molecule, a reaction catalyzed by another enzyme, phosphopyruvate dehydrogenase phosphatase. This phosphatase is stimulated by rising concentrations of Ca²⁺ ions—crucial metabolic messengers whose levels increase whenever the demand for ATP surges. Both pyruvate dehydrogenase kinase and phosphopyruvate dehydrogenase phosphatase are integral Components of the pyruvate dehydrogenase complex. The complex is therefore a highly sophisticated, autonomous, and self-regulating system.

The pyruvate dehydrogenase complex is also regulated through allosteric modulation. It is strongly inhibited not only by ATP, but also by acetyl-CoA and NADH, which are products of the pyruvate dehydrogenase reaction and simultaneously serve as allosteric Inhibitors of the system. This allosteric inhibition of pyruvate oxidation is dramatically enhanced in the presence of long-chain fatty acids; as we will learn later (Chapter 18), fatty acids likewise serve as a source of acetyl-CoA. Thus, the catalytic activity of the pyruvate dehydrogenase complex is shut down whenever Cells have an adequate supply of fuel in the form of Fatty Acids and acetyl-CoA, or when there is an elevated concentration of ATP and a high NADH/NAD⁺ ratio.