1. Glycolysis and Citric Acid Cycle Bridged via Pyruvate Dehydrogenase

2. Glycolysis are Cytosolic Enzymes While Mitochondria Complete Respiration
Pyruvate is moved from the cytosol to the mitochondrion
Matrix membrane permeability is critical

3. Citric Acid Entry Point: Acetyl CoA

4. Pyruvate Dehydrogenase Complex

5. Pyruvate Dehydrogenase Complex
Complex 4-10 million daltons with 3 distinct enzymes
Pyruvate dehydrogenase (30 nM diameter) electron micrograph

6. Acetyl Coenzyme- A Formation from Pyruvate: Three Distinct Reactions
Irreversible reaction coupling glycolysis and citric acid cycle
Enzyme complex couples the reaction steps together
What is the first reaction that looks iffy?

7. Electron Sink Needed
Thiamine pyrophosphate
(TPP) pulls in electrons

8. Step 1: E1 (PDH) Decarboxylates Pyruvate

9. Step 2: E2 Oxidizes Hydroxyethyl- to Acetyl-Dihydrolipoamide-E2
What is the structure of lipoic acid?
What reaction couples lipoic acid and lysine?

10. Step 3: E2 Oxidizes Hydroxyethyl- to Acetyl-and Transfers Acetyl- to CoA

11. Step 4-5: E3 Oxidizes Reduced Dihydrolipoamide and Reduces NAD+
Proteins tightly associated with FAD: Flavoproteins

12. Pyruvate Dehydrogenase: a Multi-Enzyme
Complex with
5 Cofactors:
CoA, NAD+,
Lipoamide,
TPP and
FAD

13. Mechanism of Pyruvate → Acetyl CoA

14. Transacetylase Core Structure (Red Balls)
Each red ball represents 3 E2 subunits
Each subunit
contains three
domains
Transacetylase domain has three subunits (1 shown in red)

15. Pyruvate Dehydrogenase Component (E1) Deactivated via Phosphorylation

16. High Energy Charge Down Regulates Pyruvate Dehydrogenase