16 glycolysis

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16 glycolysis

  1. 1. Glycolysis Embden Meyerhof pathwayo Gustav Embdeno Otto Meyerhof 1922 Nobel Prize
  2. 2. Glycolysis(glyco = sugar; lysis = to breakdown) Where do reactions of glycolysis occur in the cell? Where does the glucose (or other sugar) come from? Do these reactions need oxygen to generate energy? What is the end-product of glycolysis? Figure 4-13
  3. 3. o The glycolytic pathway is working in the cytosol of all tissues for the breakdown (oxidation) of glucose.o To provide energy (in the form of ATP) and intermediates for other metabolic pathways.o It can work in the presence of O2 (aerobic glycolysis), and in the absence of O2 (anaerobic glycolysis).
  4. 4. Aerobic glycolysiso Pyruvate is the end product of glycolysis in cells with mitochondria and an adequate supply of oxygen.o Oxygen is required to reoxidize the NADH formed during the Aerobic glycolysis, through the ETC.o Hydrogen of NADH enters the mitochondria by glycerol phosphate shuttle (producing 2 ATPs) or by malate shuttle (producing 3ATPs)
  5. 5. Anaerobic glycolysiso Allows the continued production of ATP in tissues that lack mitochondria (for example, red blood cells) or in cells deprived of sufficient oxygen (cotracting muscles).o Pyruvate, is reduced by NADH to form lactate, this allows regeneration of oxidized NAD for further reaction in the absence of O2 .
  6. 6. REACTIONS OF GLYCOLYSIS
  7. 7. The 1st investment of 1an ATP in glycolysis. CHO CHO I I HCOH HCOH I Glucokinase I HOCH(1) Preparatory phase Hexokinase HOCH I I HCOH HCOH I I HCOH ATP ADP HCOH I I CH2OH CH2O - P Glucose Glucose, 6- phosphate 1st Reaction: Glucose enters cell and is phosphorylated to glucose 6- phosphate, which is trapped inside the cell.
  8. 8. 2 CHO CH2OH I I HCOH C=O I Phosphoglucose I HOCH isomerase HOCH I I HCOH HCOH I I HCOH HCOH I I CH2O - P CH2O - P Glucose, 6- Fructose, 6- phosphate phosphate2nd Reaction: the isomerization of glucose 6-phosphate to fructose 6-phosphate. Catalyzed by phosphoglucose isomerase.
  9. 9. The 2nd investment of an ATP in glycolysis. 3 CH2OH CH2O- P I I C=O C=O I Phosphofructokinase-1 I HOCH HOCH I I HCOH HCOH I I HCOH ATP ADP HCOH I I CH2O - P CH2O - P Fructose, 6- Fructose 1,6 - phosphate bisphosphateBis means two phosphate groups on two different carbon atoms. Di meanstwo phosphate groups linked together on the same carbon atom.
  10. 10. 4 CH2O- P I C=O I CH2O- P CH2OH I C=O I Dihydroxyacetone HOCH Aldolase phosphate I HCOH I HCOH HC=O I I CH2O - P HCOH I CH2O - P Fructose 1,6 - bisphosphate Glyceraldehyde- 3 - phosphateReverse aldol condensation; converts a 6 carbon atom sugar to 2molecules, each containing 3 carbon atoms.
  11. 11. 5 Triose CH2O- P phosphate HC=O I isomerase I C=O HCOH I I CH2OH CH2O - PDihydroxyacetone Glyceraldehyde- phosphate 3 - phosphate
  12. 12. 6 O HC=O II (2) Payoff phase. CO~ P I HCOH I I HCOH CH2O - P I NAD+ + Pi NADH + H CH2O - PGlyceraldehyde, 1,3-bisphospho3-phosphate Glycerate
  13. 13. Substrate-levelphosphorylation 7 O II CO - P Phosphoglycerate HOC=O I kinase I HCOH HCOH I I CH2O - P CH2O - P ADP ATP 1,3- bisphospho 3- phospho Glycerate Glycerate 1st example of substrate level phosphorylation. The net yield from glycolysis is 2 ATP
  14. 14. 8 HOC=O phosphoglyceromutase HOC=O I I HCOH HCO - P I I CH2O - P CH2OH 3- phospho 2- phospho Glycerate GlycerateThe phosphoryl group is shifted from the C-3 to the C-2 position ofglycerate. Note: A mutase transfers a functional group from one positionto another on the same molecule.
  15. 15. 9HOC=O HOC=O I Enolase I HCO- P CO- P I II CH2OH CH2 H2O2- phospho phospho Glycerate enolpyruvate Dehydration reaction
  16. 16. Substrate-level 10phosphorylation Pyruvate HOC=O kinase HOC=O I I CO- P C=O I I CH2 CH3 ADP ATP phospho Pyruvate enolpyruvate2nd example of substrate level phosphorylation.The net yield from glycolysis is 2 ATP
  17. 17. Glucose ATP1 Glucokinase ADP Hexokinase Glucose 6-phosphate2 Phosphoglucose isomerase Fructose 6-phosphate (1) PreparatoryATP phase3 Phosphofructokinase ADP Fructose 1,6-bisphosphate4 Aldolase Dihydroxyacetone Glyceradehyde 3- phosphate phosphate Triose phosphate5 isomerase
  18. 18. Glyceraldehyde 3-phosphate NAD+ + Pi Glyceraldehyde 3-6 phosphate dehydrogenase NADH + H+ 1,3-Bisphosphoglycerate ADP7 Phosphoglycerate kinase ATP (2) Payoff phase. 3-Phosphoglycerate8 Phosphoglyceromutase 2-Phosphoglycerate9 Enolase H2O Phosphoenolpyruvate ADP10 Pyruvate kinase ATP pyruvate
  19. 19. Glucose Aerobic ATP glycolysis ATPo Glucose  2 pyruvate + 2 ATP + 2 NADH NADH NADH ATP ATP ATP ATP Pyruvate Pyruvate
  20. 20. Anaerobic Glucose glycolysis ATPo Glucose  2 ATP lactate + 2 ATP NADH + H+ NADH + H+ NAD+ NAD+ ATP ATP ATP ATPLactate Pyruvate Pyruvate Lactate
  21. 21. NAD+ NADH + H+ Glyceral- Glyceraldehyde 3-P 3-Phosphoglyceric aciddehyde 3-P (enzyme-bound) (enzyme-bound) Pi Free Enzyme 1,3-Bisphosphoglyceric acid
  22. 22. GlucoseAerobic glycolysis ATP ATP • Glucose  2 pyruvate + 2 ATP + 2 NADH NADH NADH ATP ATP ATP ATP Pyruvate Pyruvate
  23. 23. GlucoseAnaerobic glycolysis ATP • Glucose  ATP 2 Lactate + 2 ATP NADH + H+ NADH + H+ NAD+ NAD+ ATP ATP ATP ATPLactate Pyruvate Pyruvate Lactate
  24. 24. I. Energy production • Under aerobic conditions • Under anaerobic conditionsII. Importance of glycolytic intermediates 1. Pyruvate • Oxaloacetate • Acetyl CoA 2. Dihydroxyacetone phosphate (DHAP) 3. Synthesis of nonessential amino acidsIII. Importance of glycolysis in red blood cells • Energy production • Production of methemoglobin • Synthesis of 2,3-bisphosphoglycerate (2,3 BPG)IV. Gluconeogenesis
  25. 25. I- Energy production.• Under aerobic conditions glucose  2 pyruvate + 6 or 8 ATP. (according to shuttle used)• Under anaerobic conditions glucose  2 lactate + 2 ATP.
  26. 26. II- Importance of glycolytic intermediates:1. Pyruvate • Pyruvate  oxaloacetate (the prime of Krebs’ cycle) • Pyruvate  acetyl CoA • Oxidized in Krebs’ cycle for production of energy • Supply the building unit for FA and cholesterol synthesis.
  27. 27. 2. Dihydroxy acetone phosphate (DHAP) • DHAP  glycerol 3-phosphate (for synthesis of Triglyceride and phospholipids).3. Synthesis of non-essential amino acids glycine cysteine • 3- phosphoglycerate  serine • Pyruvate  alanine
  28. 28. III- Importance of glycolysis in red blood cells• Energy production• Reduction of methemoglobin by NADH-cyt b5- methemoglobin reductase• Synthesis of 2,3 bisphosphoglycerate (2,3 BPG) which units with hemoglobin at low oxygen tension and helps release of O2 to the tissues.
  29. 29. Glyceraldehyde 3-phosphate1,3 bisphosphoglycerate Bisphosphoglycerate mutaseADP Mg2+ATP Pi H2O 3- phosphoglycerate 2,3 BPG 2,3 BPG phosphatase Pyruvate
  30. 30. Deficiency of glycolytic enzymes, e.g. pyruvate kinasedeficiency (PK): • PK deficiency is restricted to RBCs and produces mild to severe chronic hemolytic anemia depending on the degree of enzyme deficiency.
  31. 31. The enzyme may show an abnormal Km or Vmx for substrates or coenzymes. Phosphoenolpyruvate ADP Pyruvate Fructose 1,6- kinase + bisphosphate ATP The enzyme mayEnzyme activity or Pyruvate show an abnormalstability may be response to thealtered, or the activator fructoseamount of enzyme Lactate 1,6-bisphosphate.may be decreased.
  32. 32. IV- Reversal of glycolysis (gluconeogenesis)• During fasting and low dietary carbohydrates glycolysis is reversed for synthesis of glucose from non-carbohydrate compounds (lactate, glycerol and amino acids). All the reactions are reversed by the same enzymes except the three irreversible kinases.
  33. 33. Regulation of glycolysis Glucose Glucagon- - Inhibition - HK GK + Insulin+ Stimulation Glucose-6- P ATP Citrate - Frucotse-6- P - Glucagon AMP PFK- Fructose-6-P + 1 + Insulin Fructose-1,6-BP Fructose-2,6-BP Glyceraldehyde-3-P Phosphoenolpyruvate - Glucagon ATP + PK - Insulin + Pyruvate
  34. 34. Effect of hormones on glycolysis1. Insulin • induces synthesis of the 3 irreversible enzymes. • Dephosphorylates the enzymes through activation of protein phosphatase.2. Glucagon • Represses (inhibit) the synthesis of the 3 irreversible enzymes. • Phosphorylates the enzymes mediated by cAMP activation of protein kinase.
  35. 35. 1- Regulation of hexokinase and glucokinase Hexokinase Glucokinase site extrahepatic Liver and pancreatic -cellsSubstrate All hexoses Glucose mainlyEnzyme kinetics • High affinity (low Km) • Low affinity (high Km) and it and it is active at low is only active at high glucose glucose concentration, concentration. So these cells which ensure supply of metabolize glucose only when glucose for tissues it is elevated. • Low Vmax • High VmaxGlucose-6- Allosteric inhibitor No effect phosphate Effect of• Insulin • No effect • Inducer (transcription of GK• Glucagon • No effect gene)• Fasting • No effect • Repressor• Feeding of • No effect • Decreases activity carbohydrates • Increases activity
  36. 36. 2- Regulation of phosphofructokinase-1 (PFK-1)• regulation by the energy levels within the cell PFK-1 allosterically inhibited by ATP and citrate.• allosterically activated by AMP and fructose 2,6-bisphosphate.
  37. 37. Glucagon Adenylate cyclase ATP cAMP Active protein kinase A Fructose 2,6- Fructose 6- bisphosphate phosphate P P ATP ADP Phosphofructo kinase-1 PFK-2 FBP-2 PFK-2 FBP-2Fructose 1,6-bisphosphate Fructose 6- phosphate Glycolysis Fasting = inhibition of glycolysis in the liver
  38. 38. Insulin Activation of many enzymes Fructose 6- Fructose 6- phosphate phosphate P P Phosphofructo PFK-2 FBP-2 PFK-2 FBP-2 kinase Fructose 1,6- bisphosphate Fructose 2,6- bisphosphate Glycolysis Feeding = activation of glycolysis in the liver
  39. 39. 3- regulation of pyruvate kinase (PK) A. Feed-forward regulation by fructose 1,6-bisphosphate. B. Covalent modification of pyruvate kinase.
  40. 40. Glucagon Receptor Adenyl cyclase ATP cAMP + PPi Active protein kinase A ADP PEP P PEP ATP ADP Pyruvate Pyruvate kinase kinase (active) (inactive)pyruvate Pi H2O Protein pyruvate + phosphatase ATPInsulin
  41. 41. Glucagon R C R C cAMP 2 CInactive protein Active protein + 2{ R -2 cAMP} kinase A kinase A ATP ADP Dephosphorylated Phosphorylated P protein protein Mg2+ Pi H2O Protein- PK a (active) phosphatase - PK b (inactive)- PFK-2a (active) - PFK-2b (inactive)- F-2,6-Bpase b (inactive) - F-2,6-BPase a (active) Activation of Insulin Inhibition of glycolysis glycolysis Insulin action Glucagon action
  42. 42. Summary
  43. 43. GlucoseAerobic glycolysis ATP ATP • Glucose  2 pyruvate + 2 ATP + 2 NADH NADH NADH ATP ATP ATP ATP Pyruvate Pyruvate
  44. 44. GlucoseAnaerobic glycolysis ATP • Glucose  ATP 2 Lactate + 2 ATP NADH + H+ NADH + H+ NAD+ NAD+ ATP ATP ATP ATPLactate Pyruvate Pyruvate Lactate
  45. 45. Regulation of glycolysis Glucose Glucagon- - Inhibition - HK GK + Insulin+ Stimulation Glucose-6- P ATP Citrate - Frucotse-6- P - Glucagon AMP PFK- Fructose-6-P + 1 + Insulin Fructose-1,6-BP Fructose-2,6-BP Glyceraldehyde-3-P Phosphoenolpyruvate - Glucagon ATP + PK - Insulin + Pyruvate

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