Catabolism of lipids, carbohydrates and the carbon skeletons of some amino acids converge on acetylCoA. AcetylCoA is a precursor for ketone bodies (acetoacetate and β-hydroxybutyrate) and for the biosynthesis of fatty acids (under anabolic conditions), and is also fed into the tricarboxylic acid cycle (TCA cycle, citric acid cycle, Krebs cycle), which generates substantial amounts of energy in the form of ATP and reduced co-factors (NADH, FADH2) which in turn generate ATP via the electron transport chain.
The Link Reaction – pyruvate dehydrogenase
Pyruvate, generated by the glycolytic pathway or from amino acid metabolism, can be transported across the inner mitochondrial membrane into the matrix and oxidatively decarboxylated to acetyl-coenzyme A (acetylCoA) by the multi-enzyme complex pyruvate dehydrogenase (PDH). The product of the reaction, acetylCoA, can enter the TCA cycle. Pyruvate dehydrogenase is regulated by phosphorylation and dephosphorylation by a dedicated kinase and phosphatase. Phosphorylation by the kinase, which is allosterically activated by high levels of ‘high-energy’ molecules (ATP, acetylCoA, NADH, inactivates PDH (Figure 10.1). In this way, PDH responds to the energy needs of the cell, only producing acetylCoA when energy, generated from the TCA cycle, is required. In skeletal muscle, calcium ions, which increase during muscle contraction, also stimulate the PDH phosphatase, which in turn activates PDH by dephosphorylation. The phosphorylation status of PDH is also regulated in the liver by the hormones insulin and glucagon. During the fed state (high blood glucose) the high insulin:glucagon ratio activates PDH phosphatase and PDH is dephosphorylated and active, the resulting acetylCoA being used in the TCA cycle or for fatty acid synthesis. During fasting/starvation the high glucagon:insulin ratio favours PDH phosphorylation and inhibition, therefore sparing pyruvate for gluconeogenesis.
The TCA cycle
In many tissues, the major fate for acetylCoA will be oxidation via the TCA cycle to CO2 and H2O (Figure 10.2). Most of these reactions take place in the mitochondrial matrix and start with condensation of acetylCoA with oxaloacetate to form citrate (citrate can act as a source of acetylCoA for fatty acid synthesis), which is then isomerised to isocitrate. The oxidative decarboxylation of isocitrate to α-ketoglutarate generates CO2 and NADH (+ H+) and the α-ketoglutarate is oxidatively decarboxylated to succinylCoA and produces another molecule of NADH. SuccinylCoA is cleaved to succinate, yielding the high-energy phosphate molecule GTP (which subsequently generates ATP), and then oxidised to fumarate, yielding FADH2. Fumarate is hydrated to form malate, which is oxidised to oxaloacetate, producing another NADH, and the oxaloacetate can accept another acetylCoA to repeat the cycle. In this way, oxaloacetate acts as a ‘carrier’ for acetate, which is completely oxidised to CO2 and H2O yielding 3 x NADH, 1 x FADH2 and 1 x GTP (=ATP). Each NADH generates around 3 ATP and the FADH2 1 ATP via the electron transport chain, so there is a yield of 12 ATP for each acetate oxidised.
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