1. Citric Acid Cycle

2. General Considerations What is the importance of citric acid cycle? final common pathway for oxidation of fuel molecules provides intermediates for biosynthesis amino acids nucleotide bases porphyrin

3. General Considerations Where in the cell does this cycle occur?

4. General Considerations What basically occurs during this cycle?

5. Formation of Acetyl Coenzyme A Importance? links glycolysis to citric acid cycle What’s involved? oxidative decarboxylation catalyzed by pyruvate dehydogenase complex three enzymes five cofactors

6. Formation of Acetyl Coenzyme A Reaction consists of three steps

7. Formation of Acetyl Coenzyme A Pyruvate dehydrogenase catalyzes the first step uses thiamine pyrophosphate (TPP) as coenzyme

8. Formation of Acetyl Coenzyme A Step 1 - Pyruvate combines with TPP and is decarboxylated

9. Formation of Acetyl Coenzyme A Next step also catalyzed by pyruvate decarboxylase and involves lipoamide

10. Formation of Acetyl Coenzyme A Step 2 – hydroxyethyl group is oxidized and acetyl group is transferred to lipoic acid

11. Step 3 – acetyl group is transferred to coenzyme A reaction catalyzed by dihydrolipoyl transacetylase Formation of Acetyl Coenzyme A

12. Step 4 – lipoamide is regenerated and electrons are transferred to FAD and NAD + catalyzed by dihyrolipoyl dehdrogenase

13. Formation of Acetyl Coenzyme A

14. Model of pyruvate dehydrogenase complex

15. Formation of Acetyl Coenzyme A

16. Synthesis of Citrate How is citrate formed? What kind of reaction is this?

17. Synthesis of Citrate How does citrate synthase catalyze this reaction? binding of oxaloacetate causes structural rearrangement binding site for acetyl CoA forms catalysis via proximity of substrates

18. Synthesis of Citrate

20. Formation of Isocitrate Isomerization of citrate occurs by a dehydration followed by a hydration catalyzed by aconitase

21. Aconitase is an iron-sulfur protein Formation of Isocitrate

22. Formation of  -Ketoglutarate Isocitrate is oxidized and decarboxylated to  - ketoglutarate isocitrate dehydrogenase

23. Formation of Succinyl CoA Oxidative decarboxylation of  -ketoglutarate uses same mechanism as conversion of pyruvate to acetyl CoA  -ketoglutarate dehdrogenase complex

24. Formation of Succinate Cleavage of thioester bond coupled to formation of GTP substrate level phosphorylation succinyl CoA synthetase

25. Regeneration of Oxaloacetate oxidation of succinate – succinate dehydrogenase iron-sulfur protein hydration of fumarate – fumarase oxidation of malate – malate dehydrogenase

26. Summary of Citric Acid Cycle

27. Regulation of Pyruvate Dehdrogenase Complex end-product inhibition covalent modification energy charge hormones &  1 adrenergic agonists via Ca ++

28. Control of Citric Acid Cycle allostric enzymes are at primary control points  -ketoglutarate dehydrogenase isocitrate dehydrogenase pyruvate dehydrogenase

29. Intermediates for Biosynthesis

30. Citric Acid Cycle How is oxaloacetate replenished to keep CAC going? carboxylation of pyruvate energy charge influences use of OAA high – converted to glucose low – converted to citrate

31. Clinical Applications What is beriberi and what causes it? nutritional deficiency of thiamine leading to neurological and cardiovascular problems? What specifically causes the problems? Why does arsenic or mercury poisoning cause similar symptoms? binds lipoamide

32. Glyoxylate Cycle What is this cycle and who uses it? metabolic cycle for utilization of acetate plants and bacteria