BC21D: Bioenergetics & Metabolism

1. BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A: • Pyruvate dehydrogenase • -oxidation • Amino acid catabolism andrew.pearson@uwimona.edu.jm

2. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Pyruvate and acetyl CoA are important metabolites at the intersection of many carbon-metabolising pathways.

3. Metabolic relationship between carbohydrate and fat catabolism Pyruvate Carboxylase Pyruvate Dehydrogenase Complex

4. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Let us look at pyruvate first.

5. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Pyruvate is the normal 3-carbon product of carbohydrate catabolism

6. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 1. Glycolysis by either the EMP pathway, or variants such as PPP/HMP.

7. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 1. Glycolysis by either the EMP pathway, or variants such as PPP/HMP.

8. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism These fermentative pathways have PK as the last enzyme.

9. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Recall that PK is an important regulatory enzyme in some cells.

10. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Apart from being the normal product of carbohydrate fermentative catabolism, pyruvate is often produced by two other metabolic circumstances……..

11. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 2. Aerobic oxidation of lactate, e.g. by heart or liver isoenzymes of Lactate dh.

12. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 2. Aerobic oxidation of lactate, e.g. by heart or liver isoenzymes of Lactate dh.

13. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 3. Oxidative deamination of alanine, e.g. by liver after release from skeletal muscle during fasting.

14. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism 3. Oxidative deamination of alanine, e.g. by liver after release from skeletal muscle during fasting.

15. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Lets us now look at pyruvate dehydrogenase

16. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism

17. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism

18. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism

19. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism pdh reaction mechanism

20. BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A pdh reaction mechanism

21. decarboxylation

23. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Pdh is regulated by reversible, inhibitory phosphorylation of E1.

24. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Pdh is regulated by 4 reversible, inhibitory kinases of E1. The kinases have differing tissue specificities. The kinases are activated by increasing the ratios of: [NADH]/[NAD]; [acetyl CoA]/[CoA]; [ATP]/[ADP] The kinases are inhibited by pyruvate. Insulin stimulates dephosphorylyation.

25. Regulation of the Pyruvate Dehydrogenase Complex Pyruvate dehydrogenase phosphatase “Pyruvate dehydrogenase kinase”, actually…. Pyruvate dehydrogenase complex Pyruvate dehydrogenase kinases 1 – 4, with different tissue specificities Phosphorylation sites on Pdh subunit E1

26. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Apart from carbohydrates, carbons from other molecules can form acetyl CoA. CHO

27. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Parts of leucine isoleucine tryptophan are degraded to acetyl CoA

28. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Lets us now look at fatty acid degradation

29. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism

30. Figure 3 Modulation of CPT I activity by carbohydrates The pathway shown in red is the established pathway for the inhibition of hepatic CPT activity by carbohydrates. The other pathways shown are alternative routes that may be operative in heart Abbreviations : CPT, carnitine palmitoyl transferase ; CAT, carnitine acetyl transferase. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism

31. The formation of Acetyl Coenzyme A BC21D: Bioenergetics & Metabolism Just to remind you where we are going with this!