Pyruvate dehydrogenase and the citric acid cycle

Pyruvate degradation occurs in the mitochondria

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

The structural organization of the PDH complex

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

The pyruvate dehydrogenase reaction involves multiple coenzymes Subunit Role in catalysis thiamine pyrophosphate E1 provides a carbanion for nucleophilic attack on the substrate lipoamide E2 transfers substrate to coenzyme A, retains hydrogen flavin adenine dinucleotide (FAD) E3 transfers H2 from lipoamide to NAD+

Thiamine pyrophosphate forms a carbanion

Decarboxylation of pyruvate by E1

Release of acetyl-CoA and disposal of hydrogen

Alternate metabolic destinations of pyruvate conversion to acetyl-CoA by PDH for complete degradation or for synthesis of fatty acids and cholesterol carboxylation to oxaloacetate, for use in gluconeogenesis or in the citric acid cycle synthesis of amino acids, e.g., transamination to alanine reduction to lactate

Regulation of PDH by allosteric effectors and by phosphorylation

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

The citrate synthase reaction

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

Reactions in the TCA: from succinyl-CoA to oxaloacetate

α-Ketoglutarate dehydrogenase resembles PDH

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