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Citric Acid Cycle

Citric Acid Cycle. 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. General Considerations. Where in the cell does this cycle occur?.

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Citric Acid Cycle

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

  12. Formation of Acetyl Coenzyme A • Step 4 – lipoamide is regenerated and electrons are transferred to FAD and NAD+ • catalyzed by dihyrolipoyl dehdrogenase

  13. Formation of Acetyl Coenzyme A

  14. Formation of Acetyl Coenzyme A • 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

  19. Synthesis of Citrate

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

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

  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 & 1adrenergic 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

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