ABSTRACT
Introduction...................................................................................................... 149 Structure and Catalytic Mechanism of Pyruvate Dehydrogenase Complex ... 151 Regulation of PDC by Phosphorylation=Dephosphorylation .......................... 154 Mechanism of Phosphorylation=Dephosphorylation of PDC...................... 154 Regulation of Phosphorylation=Dephosphorylation of PDC....................... 156
Effect of Lipoic Acid on Glucose Metabolism and PDC................................ 157 Effect of Lipoic Acid on Glucose Uptake ................................................... 157 Effect of Lipoic Acid on PDC Components................................................ 158
Concluding Remarks........................................................................................ 161 References ........................................................................................................ 162
Dietary carbohydrates provide at least one-third of daily caloric intake in Westernized societies. This calorie contribution of carbohydrates is even higher (>50%) in some populations in developing countries due to relatively low costs and availability. Hence the metabolism of glucose via the glycolytic pathway and the tricarboxylic acid cycle represents a major metabolic scheme for generation of energy. These two pathways are directly linked by the pyruvate dehydrogenase complex (PDC) localized in the mitochondria (Figure 6.1). Pyruvate derived from glucose via the glycolytic pathway is oxidatively decarboxylated to acetyl-CoA by PDC. Acetyl-CoA is further metabolized for
energy production via the tricarboxylic acid cycle or utilized for biosynthesis of lipids. Pyruvate dehydrogenase complex catalyzes the only known reaction in higher eukaryotes to generate acetyl-CoA from pyruvate and since the PDC reaction is irreversible, the flux through PDC is highly regulated to maintain glucose homeostasis and to meet the metabolic needs of different tissues during the fed and fasted states. Regulation of PDC activity in mammals is accomplished by sophisticated mechanisms involving both covalent modification and transcriptional mechanisms. Insulin is a central hormone in regulating glucose
FIGURE 6.1 The suggested effects of lipoic acid on glucose metabolism. The positive (upward thick arrows) and negative (downward thick arrows) effects of lipoic acid in its oxidized or reduced form are shown as thick arrows. ROS, reactive oxygen species; IR, insulin receptor; IRS, insulin receptor substrate-1; GLUT4, glucose transporter 4; PI3K, phosphatidylinositol 3-kinase; PKB=Akt, protein kinase B=Akt1; p38, p38 mitogenactivated protein kinase; and PKCl=d, protein kinase C isoforms l and d.
