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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. Glycolysis.

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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. Glycolysis Figure 15-1

  5. Stage I of Glycolysis(Energy Investment) 2X

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

  7. Stage II of Glycolysis(Energy Recovery) Substrate Level Phosphorylation —> Serine, Cysteine and Glycine —> Aromatic Amino Acids —> Alanine Substrate Level Phosphorylation

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

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

  10. Reactions of GlycolysisStage I

  11. Hexokinase(First Use of ATP) Go’ (kJ/mol) G (kJ/mol) Glucose + Pi G-6-P + H2O 13.8 20.5 ATP + H2O  ADP + Pi -30.5 -54.4 Glucose + ATP  G-6-P + ADP -16.7 -33.9 NOTE: Lack of Specificity

  12. Role of Mg2+ Page 489

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

  14. Results of Conformational Change • Formation of ATP binding site • Exclusion of water • Increased nucleophilicity of CH2OH • Proximity effect

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

  16. 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

  17. 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

  18. Hexokinase versus Glucokinase Figure 22-4

  19. Metabolism of Glucose-6-P Regulation!

  20. Phosphoglucose Isomerase Go’ (kJ/mol) G (kJ/mol) Glucose-6-phosphate Fructose-6-phosphate 2.2 -1.4

  21. Reaction Mechanism of Phosphoglucose Isomerase

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

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

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

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

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

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

  28. Phosphofructokinase(Second Use of ATP) Go’ (kJ/mol) G (kJ/mol) F-6-P + Pi F-1,6-bisP + H2O 16.3 36.0 ATP + H2O  ADP + Pi -30.5 -54.4 F-6-P + ATP  F-1,6-bisP + ADP -14.2 -18.8 NOTE: bisphosphate versus diphosphate

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

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

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

  32. Formation and Degradation of -D-Fructose-2,6-bisP High glucose Low glucose

  33. Carbon # from glucose Aldolase 1 2 3 4 5 6 Go’ (kJ/mol) G (kJ/mol) F-1,6-bisP  GAP + DHAP 23.8 ~0

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

  35. Enzymatic Mechanism of Aldolase

  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 Go’ (kJ/mol) G (kJ/mol) DHAP  GAP 7.5 ~0

  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 DehydrogenaseGAPDH 3,4 2,5 1,6 Go’ (kJ/mol) G (kJ/mol) GAP + NAD+ H2O  3-PG + NADH + H+ -43.1 36.0 3PG + Pi  1,3-BPG + H2O 49.4 -54.4 GAP + NAD+ + Pi  1,3-BPG + NADH + H+ 6.3 -18.8

  48. Acylphosphate

  49. Enzymatic Mechanism ofGlyceraldehyde-3-P Dehydrogenase

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

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