Pyruvate degradation occurs in the mitochondria

© Michael Palmer 2014

The PDH reaction occurs in three successive steps that are catalyzed by three different subunits

© Michael Palmer 2014

The structural organization of the PDH complex

© Michael Palmer 2014

A lipoamide tether guides the substrate from one active site to the next

© Michael Palmer 2014

The pyruvate dehydrogenase reaction involves multiple coenzymes

© Michael Palmer 2014

Thiamine pyrophosphate forms a carbanion

© Michael Palmer 2014

Decarboxylation of pyruvate by E1

© Michael Palmer 2014

Release of acetyl-CoA and disposal of hydrogen

© Michael Palmer 2014

Alternate metabolic destinations of pyruvate

1. conversion to acetyl-CoA by PDH for complete degradation or for synthesis of fatty acids and cholesterol

2. carboxylation to oxaloacetate, for use in gluconeogenesis or in the citric acid cycle

3. synthesis of amino acids, e.g., transamination to alanine

4. reduction to lactate

Regulation of PDH by allosteric effectors and by phosphorylation

© Michael Palmer 2014

The overall reaction of the TCA cycle: does it add up?

© Michael Palmer 2014

The citrate synthase reaction

© Michael Palmer 2014

Reactions in the TCA cycle: from citrate to succinyl-CoA

© Michael Palmer 2014

Reactions in the TCA: from succinyl-CoA to oxaloacetate

© Michael Palmer 2014

α-Ketoglutarate dehydrogenase resembles PDH

© Michael Palmer 2014

Regulation of the citric acid cycle

● ATP and NADH inhibit isocitrate dehydrogenase ● NADH inhibits α-ketoglutarate dehydrogenase ● High levels of NADH will lower the oxaloacetate

concentration, which limits citrate synthase activity