16 glycolysis

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<ul><li>1.Glycolysis Embden Meyerhof pathwayo Gustav Embdeno Otto Meyerhof1922 Nobel Prize</li></ul> <p>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. o The glycolytic pathway is working in the cytosol ofall tissues for the breakdown (oxidation) of glucose.o To provide energy (in the form of ATP) andintermediates for other metabolic pathways.o It can work in the presence of O2 (aerobicglycolysis), and in the absence of O2 (anaerobicglycolysis). 4. Aerobic glycolysiso Pyruvate is the end product of glycolysis in cellswith mitochondria and an adequate supply ofoxygen.o Oxygen is required to reoxidize the NADH formedduring the Aerobic glycolysis, through the ETC.o Hydrogen of NADH enters the mitochondria byglycerol phosphate shuttle (producing 2 ATPs) orby malate shuttle (producing 3ATPs) 5. Anaerobic glycolysiso Allows the continued production of ATP intissues that lack mitochondria (for example, redblood cells) or in cells deprived of sufficientoxygen (cotracting muscles).o Pyruvate, is reduced by NADH to form lactate,this allows regeneration of oxidized NAD forfurther reaction in the absence of O2 . 6. REACTIONS OF GLYCOLYSIS 7. The 1st investment of1an ATP in glycolysis.CHOCHOII HCOH HCOHIGlucokinase IHOCH(1) Preparatory phase HexokinaseHOCHII HCOH HCOHII HCOHATPADP HCOHIICH2OHCH2O - PGlucose Glucose, 6-phosphate1st Reaction: Glucose enters cell and is phosphorylated to glucose 6-phosphate, which is trapped inside the cell. 8. 2CHO CH2OHI I HCOH C=OI PhosphoglucoseIHOCHisomerase HOCHI I HCOHHCOHI I HCOHHCOHI ICH2O - PCH2O - PGlucose, 6-Fructose, 6-phosphatephosphate2nd Reaction: the isomerization of glucose 6-phosphate to fructose 6-phosphate. Catalyzed by phosphoglucose isomerase. 9. The 2nd investment of an ATP in glycolysis. 3 CH2OH CH2O- P I I C=O C=O IPhosphofructokinase-1I HOCHHOCH I IHCOHHCOH I IHCOH ATPADP HCOH I I CH2O - PCH2O - P Fructose, 6- Fructose 1,6 - phosphatebisphosphateBis means two phosphate groups on two different carbon atoms. Di meanstwo phosphate groups linked together on the same carbon atom. 10. 4CH2O- PIC=OICH2O- P CH2OHIC=OI DihydroxyacetoneHOCH AldolasephosphateI HCOHI HCOHHC=OI ICH2O - P HCOHICH2O - PFructose 1,6 -bisphosphate Glyceraldehyde- 3 - phosphateReverse aldol condensation; converts a 6 carbon atom sugar to 2molecules, each containing 3 carbon atoms. 11. 5 TrioseCH2O- PphosphateHC=OIisomerase IC=O HCOHIICH2OHCH2O - PDihydroxyacetone Glyceraldehyde- phosphate 3 - phosphate 12. 6OHC=OII(2) Payoff phase. CO~ P IHCOH I I HCOH CH2O - PINAD+ + Pi NADH + H CH2O - PGlyceraldehyde, 1,3-bisphospho3-phosphateGlycerate 13. Substrate-levelphosphorylation7 O II CO - P Phosphoglycerate HOC=O Ikinase IHCOHHCOH I I CH2O - PCH2O - PADPATP1,3- bisphospho3- phospho GlycerateGlycerate1st example of substrate level phosphorylation. The net yield from glycolysis is 2 ATP 14. 8HOC=OphosphoglyceromutaseHOC=OII HCOH HCO - PIICH2O - P CH2OH3- phospho2- 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. 9HOC=OHOC=OI Enolase I HCO- PCO- PIIICH2OHCH2H2O2- phospho phospho Glycerate enolpyruvateDehydration reaction 16. Substrate-level 10phosphorylation Pyruvate HOC=OkinaseHOC=O II CO- PC=O II CH2CH3ADP ATP phospho Pyruvate enolpyruvate2nd example of substrate level phosphorylation.The net yield from glycolysis is 2 ATP 17. Glucose ATP1GlucokinaseADP Hexokinase Glucose 6-phosphate2Phosphoglucose isomeraseFructose 6-phosphate (1) PreparatoryATP phase3Phosphofructokinase ADP Fructose 1,6-bisphosphate4AldolaseDihydroxyacetoneGlyceradehyde 3- phosphate phosphate Triose phosphate5isomerase 18. Glyceraldehyde 3-phosphate NAD+ + PiGlyceraldehyde 3-6phosphate dehydrogenaseNADH + H+ 1,3-BisphosphoglycerateADP7 Phosphoglycerate kinaseATP (2) Payoff phase. 3-Phosphoglycerate8Phosphoglyceromutase 2-Phosphoglycerate9 EnolaseH2OPhosphoenolpyruvateADP10 Pyruvate kinaseATPpyruvate 19. Glucose Aerobic ATPglycolysis ATPo Glucose 2 pyruvate + 2 ATP + 2 NADH NADH NADH ATP ATPATPATPPyruvate Pyruvate 20. AnaerobicGlucoseglycolysis ATPo Glucose 2ATPlactate + 2 ATP NADH + H+ NADH + H+NAD+NAD+ATPATPATPATPLactate Pyruvate PyruvateLactate 21. NAD+ NADH + H+ Glyceral-Glyceraldehyde 3-P3-Phosphoglyceric aciddehyde 3-P (enzyme-bound)(enzyme-bound) PiFree Enzyme 1,3-Bisphosphoglyceric acid 22. GlucoseAerobic glycolysisATPATP Glucose 2 pyruvate+ 2 ATP+ 2 NADH NADHNADHATP ATP ATP ATP Pyruvate Pyruvate 23. GlucoseAnaerobic glycolysisATP Glucose ATP 2 Lactate + 2 ATPNADH + H+ NADH + H+ NAD+NAD+ ATPATP ATPATPLactatePyruvate PyruvateLactate 24. I.Energy productionUnder aerobic conditionsUnder anaerobic conditionsII. Importance of glycolytic intermediates1. Pyruvate Oxaloacetate Acetyl CoA2. Dihydroxyacetone phosphate (DHAP)3. Synthesis of nonessential amino acidsIII. Importance of glycolysis in red blood cellsEnergy productionProduction of methemoglobinSynthesis of 2,3-bisphosphoglycerate (2,3 BPG)IV. Gluconeogenesis 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. 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 cholesterolsynthesis. 27. 2. Dihydroxy acetone phosphate (DHAP) DHAP glycerol 3-phosphate (for synthesis of Triglyceride and phospholipids).3. Synthesis of non-essential amino acids glycinecysteine 3- phosphoglycerate serine Pyruvate alanine 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 tensionand helps release of O2 to the tissues. 29. Glyceraldehyde 3-phosphate1,3 bisphosphoglycerateBisphosphoglyceratemutaseADPMg2+ATPPiH2O 3- phosphoglycerate2,3 BPG 2,3 BPG phosphatase Pyruvate 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. The enzyme mayshow an abnormalKm or Vmx forsubstrates orcoenzymes.PhosphoenolpyruvateADP Pyruvate Fructose 1,6- kinase + bisphosphateATPThe enzyme mayEnzyme activity orPyruvateshow an abnormalstability may beresponse to thealtered, or the activator fructoseamount of enzymeLactate 1,6-bisphosphate.may be decreased. 32. IV- Reversal of glycolysis (gluconeogenesis) During fasting and low dietary carbohydratesglycolysis is reversed for synthesis of glucose fromnon-carbohydrate compounds (lactate, glycerol andamino acids). All the reactions are reversed by thesame enzymes except the three irreversible kinases. 33. Regulation of glycolysisGlucose Glucagon-- Inhibition-HK GK +Insulin+ Stimulation Glucose-6- P ATP Citrate - Frucotse-6- P - GlucagonAMPPFK-Fructose-6-P + 1 + InsulinFructose-1,6-BP Fructose-2,6-BP Glyceraldehyde-3-P Phosphoenolpyruvate - GlucagonATP+ PK - Insulin +Pyruvate 34. Effect of hormones on glycolysis1. Insulin induces synthesis of the 3 irreversible enzymes. Dephosphorylates the enzymes through activationof protein phosphatase.2. Glucagon Represses (inhibit) the synthesis of the 3irreversible enzymes. Phosphorylates the enzymes mediated by cAMPactivation of protein kinase. 35. 1- Regulation of hexokinase and glucokinaseHexokinase Glucokinase site extrahepaticLiver and pancreatic -cellsSubstrate All hexoses Glucose mainlyEnzyme kinetics High affinity (low Km) Low affinity (high Km) and itand it is active at low is only active at high glucoseglucose concentration,concentration. So these cellswhich ensure supply ofmetabolize glucose only whenglucose for tissues it is elevated. Low Vmax High VmaxGlucose-6-Allosteric inhibitorNo 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. 2- Regulation of phosphofructokinase-1 (PFK-1) regulation by the energy levels within the cell PFK-1 allostericallyinhibited by ATP and citrate. allosterically activated by AMP and fructose 2,6-bisphosphate. 37. Glucagon Adenylatecyclase ATP cAMP Active protein kinase AFructose 2,6- Fructose 6-bisphosphate phosphate PPATP ADP Phosphofructo kinase-1PFK-2 FBP-2PFK-2 FBP-2Fructose 1,6-bisphosphateFructose 6- phosphate GlycolysisFasting = inhibition of glycolysis in the liver 38. InsulinActivation of many enzymesFructose 6- Fructose 6-phosphate phosphatePP PhosphofructoPFK-2 FBP-2 PFK-2 FBP-2kinaseFructose 1,6-bisphosphate Fructose 2,6- bisphosphate GlycolysisFeeding = activation of glycolysis in the liver 39. 3- regulation of pyruvate kinase (PK) A. Feed-forward regulation by fructose 1,6-bisphosphate. B. Covalent modification of pyruvate kinase. 40. GlucagonReceptorAdenylcyclaseATPcAMP + PPiActive protein kinase A ADP PEPPPEPATP ADPPyruvatePyruvatekinasekinase (active) (inactive)pyruvatePi H2O Proteinpyruvate+ phosphataseATPInsulin 41. GlucagonRCRCcAMP2 CInactive proteinActive protein+ 2{ R-2 cAMP} kinase A kinase A ATP ADPDephosphorylatedPhosphorylatedPproteinproteinMg2+ Pi H2OProtein- 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 ofInsulinInhibition of glycolysisglycolysisInsulin actionGlucagon action 42. Summary 43. GlucoseAerobic glycolysisATPATP Glucose 2 pyruvate+ 2 ATP+ 2 NADH NADHNADHATP ATP ATP ATP Pyruvate Pyruvate 44. GlucoseAnaerobic glycolysisATP Glucose ATP 2 Lactate + 2 ATPNADH + H+ NADH + H+ NAD+NAD+ ATPATP ATPATPLactatePyruvate PyruvateLactate 45. Regulation of glycolysisGlucose Glucagon-- Inhibition-HK GK +Insulin+ Stimulation Glucose-6- P ATP Citrate - Frucotse-6- P - GlucagonAMPPFK-Fructose-6-P + 1 + InsulinFructose-1,6-BP Fructose-2,6-BP Glyceraldehyde-3-P Phosphoenolpyruvate - GlucagonATP+ PK - Insulin +Pyruvate </p>