1. Pyruvate dehydrogenase and the citric acid cycle

2. Pyruvate degradation occurs in the mitochondria

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

4. The structural organization of the PDH complex

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

6. 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+

7. Thiamine pyrophosphate forms a carbanion

8. Decarboxylation of pyruvate by E1

9. Release of acetyl-CoA and disposal of hydrogen

10. 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

11. Regulation of PDH by allosteric effectors and by phosphorylation

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

13. The citrate synthase reaction

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

15. Reactions in the TCA: from succinyl-CoA to oxaloacetate

16. α-Ketoglutarate dehydrogenase resembles PDH

17. 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