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Glycolysis

Glycolysis. Anaerobic degradation of glucose to yield lactate or ethanol and CO 2. Learning Objectives. Sequence of Reactions Metabolites Enzymes Enzyme Mechanisms Energetics Regulation. Overview of Glycolysis. Glucose (C 6 ) —> 2 Pyruvate (C 3 ) 2 ADP + 2 P i —> 2 ATP.

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Glycolysis

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  1. Glycolysis Anaerobic degradation of glucose to yield lactate or ethanol and CO2

  2. Learning Objectives • Sequence of Reactions • Metabolites • Enzymes • Enzyme Mechanisms • Energetics • Regulation

  3. Overview of Glycolysis Glucose (C6) —> 2 Pyruvate (C3) 2 ADP + 2 Pi —> 2 ATP

  4. Effect of Inhibitors

  5. Glycolysis Figure 15-1

  6. Stage I of Glycolysis(Energy Investment)

  7. Summary of Stage I Glucose + 2 ATP ——> 2 GA3P + 2 ADP + 2 H+

  8. Stage II of Glycolysis(Energy Recovery) Substrate Level Phosphorylation

  9. Stage II of Glycolysis(Energy Recovery) 3PGA —> Serine, Cysteine and Glycine PEP —> Aromatic Amino Acids

  10. Stage II of Glycolysis(Energy Recovery) Substrate Level Phosphorylation Pyruvate —> Alanine

  11. Summary of Stage II 2 GA3P + 2 NAD+ + 4 ADP + 2 Pi 2 Pyruvate + 2 NADH + 2 H+ + 4 ATP

  12. Summary of Glycolysis Glucose + 2 NAD+ + 2 ADP + 2 Pi 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP NOTE: NAD+ must be regenerated!

  13. Reactions of GlycolysisStage I

  14. Hexokinase(First Use of ATP) NOTE: Lack of Specificity

  15. Role of Mg2+ Page 489

  16. Substrate-induced Conformational Changes in Yeast Hexokinase Figure 15-2

  17. Results of Conformational Change • Exclusion of water • Increased nucleophilicity of CH2OH • Proximity effect

  18. Regulation of Hexokinase Inhibition by glucose-6-P Impermeability

  19. Hexokinase versus Glucokinase • Hexokinase (all tissues) • Non-specific • KM = ~100 µM • Inhibited by glucose-6-P • Glucokinase (primarily in liver) • Specific • KM = ~10 mM • Not inhibited by glucose-6-P

  20. Functional Rationale • Most tissues: metabolize blood glucose which enters cells • Glc-6-P impermeable to cell membrane • Product inhibition • Liver: maintain blood glucose • High blood glucose: glycogen • Low blood glucose: glycolysis

  21. Hexokinase versus Glucokinase Figure 22-4

  22. Metabolism of Glucose-6-P Regulation!

  23. Phosphoglucose Isomerase

  24. Reaction Mechanism of Phosphoglucose Isomerase(Substrate Binding) Figure 15-3 part 1

  25. Reaction Mechanism of Phosphoglucose Isomerase(Acid-Catalyzed Ring Opening) Figure 15-3 part 2

  26. Reaction Mechanism of Phosphoglucose Isomerase(Formation of cis-enediolate Intermediate) Figure 15-3 part 3

  27. Reaction Mechanism of Phosphoglucose Isomerase(Proton Transfer) Figure 15-3 part 4

  28. Reaction Mechanism of Phosphoglucose Isomerase(Base-Catalyzed Ring Closure) Figure 15-3 part 5

  29. Reaction Mechanism of Phosphoglucose Isomerase(Product Release) Figure 15-3 part 1

  30. Phosphofructokinase(Second Use of ATP) NOTE: bisphosphate versus diphosphate

  31. Characteristics of Reaction Catalyzed by PFK • Rate-determining reaction • Reversed by Fructose-1,6-bisphosphatase • Mechanism similar to Hexokinase

  32. Regulatory Properties of PFK • Main control point in glycolysis • Allosteric enzyme • Positive effectors • AMP • Fructose-2,6-bisphosphate • Negative effectors • ATP • Citrate

  33. -D-Fructose-2,6-Bisphosphate Page 558

  34. Aldolase

  35. Mechanism of Base-Catalyzed Aldol Cleavage NOTE: requirement for C=O at C2 Rationale for Phosphoglucose Isomerase Figure 15-4

  36. Enzymatic Mechanism of Aldolase(Substrate Binding) Figure 15-5 part 1

  37. Enzymatic Mechanism of Aldolase(Schiff Base (imine) Formation) Figure 15-5 part 2

  38. Enzymatic Mechanism of Aldolase(Aldol Cleavage) Figure 15-5 part 3

  39. Enzymatic Mechanism of Aldolase(Tautomerization and Protonation) Figure 15-5 part 4

  40. Enzymatic Mechanism of Aldolase(Schiff Base Hydrolysis and Product Release) Figure 15-5 part 5

  41. Triose Phosphate Isomerase

  42. Enzymatic Mechanism ofTriose Phosphate Isomerase Part 494

  43. Transition State Analog Inhibitors ofTriose Phosphate Isomerase Part 494

  44. Schematic Diagram of the First Stage of Glycolysis Figure 15-7

  45. Summary of Stage I Glucose + 2 ATP ——> 2 GA3P + 2 ADP + 2 H+

  46. Reactions of GlycolysisStage II

  47. Glyceraldehyde-3-P Dehydrogenase

  48. Coupled Reactions

  49. Acylphosphate

  50. Enzymatic Mechanism ofGlyceraldehyde-3-P Dehydrogenase(Substrate Binding) Figure 15-9 part 1

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