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BC368 : Biochemistry of the Cell II

BC368 : Biochemistry of the Cell II. Citric Acid Cycle Chapter 16 March 13, 2014. 3 stages of respiration. Production of acetyl-CoA (e.g., during glycolysis and the bridging reaction) Oxidation of acetyl-CoA via the citric acid cycle

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BC368 : Biochemistry of the Cell II

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  1. BC368: Biochemistry of the Cell II Citric Acid Cycle Chapter 16 March 13, 2014

  2. 3 stages of respiration • Production of acetyl-CoA (e.g., during glycolysis and the bridging reaction) • Oxidation of acetyl-CoA via the citric acid cycle • Electon transport and oxidative phosphorylation to produce lots of ATP Fig 16-1

  3. Mitochondrial Architecture • Glycolysis takes place in the cytosol • The citric acid cycle takes place in the mitochondrial matrix

  4. The Bridging Reaction H+ +

  5. The Bridging Reaction Fig 16-2

  6. The Bridging Reaction • E1: orange • E2: green • E3: yellow

  7. Pyruvate dehydrogenase complex 1. Decarboxylation 2. Oxidation 3. Acetyl group to CoA 4. Restore enzyme Fig 16-6 Fig 16-6

  8. Pyruvate dehydrogenase complex Step 1. Decarboxylation Fig 16-6 Fig 16-6

  9. TPP Cofactor • TPP is derived from vitamin B1 • Common for decarboxylation reactions • Carries carbon groups transiently Fig 14-15

  10. Pyruvate dehydrogenase complex Step 2. Oxidation, with reduction of E2 Fig 16-6 Fig 16-6

  11. Lipoic Acid “Swinging Arm” • Swinging arm acyl group carrier • Transfers intermediates between different enzyme sites of interest here

  12. The Marsh Test

  13. Pyruvate dehydrogenase complex Step 3. Transfer to CoA Fig 16-6 Fig 16-6

  14. Coenzyme A • Derived from Vitamin B5 (pantothenic acid) • “Activates” the acetyl group Fig 16-3

  15. Pyruvate dehydrogenase complex Step 4. Oxidation of enzyme Fig 16-6 Fig 16-6

  16. FAD/FADH2 • Derived from Vitamin B2 (riboflavin) • 1 or 2 electron acceptor

  17. NAD+/NADH • Derived from Vitamin B3 (niacin) • 2 electron acceptor

  18. Pyruvate dehydrogenase complex Fig 16-6 Fig 16-6

  19. Coenzyme A • Acetyl group is activated in two ways: • Carbonyl carbon is activated for attack by nucleophiles • Methyl carbon is more acidic Fig 16-3

  20. The Citric Acid Cycle

  21. Reaction 1: Condensation

  22. Citrate synthase mechanism 1. deprotonation of methyl group of acetyl-CoA Fig 16-9

  23. Citrate synthase mechanism 2. enolate attacks carbonyl of OA, forming citroyl-CoA Fig 16-9

  24. Citrate synthase mechanism 3. hydrolysis of thioester releases citrate and CoA Fig 16-9

  25. Reaction 2: Isomerization

  26. A symmetric molecule that acts asymmetric! Chemically, these carbons are identical!

  27. A symmetric molecule that acts asymmetric! Chemically, these carbons are identical! So both these products should be formed

  28. A symmetric molecule that acts asymmetric! Chemically, these carbons are identical! So both these products should be formed

  29. Prochiral molecules can act chiral!

  30. Reaction 3: Oxidative Decarboxylation

  31. Reaction 4: Oxidative Decarboxylation

  32. Reaction 5: Substrate-level phosphorylation

  33. Succinyl-CoA synthetase reaction • Hydrolysis of CoA-SH drives phosphorylation of succinate within the enzyme-substrate complex • Succinate transfers its phosphate group to the enzyme • Enzyme phosphorylates GDP

  34. Reactions 6, 7, and 8 • Oxidation • Hydration • Oxidation

  35. Summary of TCA Fig 16-14

  36. Regulation • Irreversible reactions are regulated • In general, energy charge is key: • AMP/NAD+ activate • ATP/NADH inhibit • Product inhibition Fig 16-19

  37. Anaplerotic Reactions Fig 16-16

  38. Anaplerotic Reactions • Example: pyruvate carboxylase, which uses a biotin (vitamin B7) cofactor to carry CO2

  39. Case Study Daniel plans to enter the Mr. Colby contest and wants to get jacked. He has begun adding raw eggs to his diet and is up to a dozen a day. Unfortunately, he has been experiencing lactic acidosis during his weight training and hypoglycemia between meals. What’s up with Daniel?

  40. Case Study KD ≈ 10-15 M

  41. Pyruvate carboxylase Carboxyl group of bicarbonate is “activated” by phosphorylation

  42. Pyruvate carboxylase “Activated” CO2 is passed to biotin cofactor with loss of Pi

  43. Pyruvate carboxylase CO2 is passed to second active site for rxn with pyruvate

  44. Pyruvate carboxylase CO2 is released for reaction with pyruvate to form OA.

  45. Glyoxylate cycle • Plants and some microorganisms can convert acetyl-CoA to oxaloacetate for net gain of carbon and net synthesis of TCA intermediates Fig 16-22

  46. Intersection with TCA • Glyxoylate pathway runs simultaneously with TCA but in a different compartment. Fig 16-24

  47. Coordinated regulation • Isocitrate is a branch point; its fate depends on relative activities of isocitrate dehydrogenase (TCA) and isocitrate lyase (glyoxylate cycle). Fig 16-25

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