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Unformatted text preview: Chapter 17GlycolysisMajor pathways of glucose metabolismGlycolysisGlucose + 2NAD+ + 2ADP + 2Pi 2Pyruvate + 2NADH + 2ATP + 2H2O + 4H+ Common metabolicpathway conservedthroughout almostall living organisms Conversion ofglucose (C6) to twopyruvate (C3) 10 enzymaticreactions The generation of 2ATP and 2 NADHper glucoseGlycolytic pathway overviewChemical strategy of glycolysis Phosphoryl transfer to the glucose Conversion of phosphorylated intermediates tohigh-energy compounds ATP synthesis coupled with the phosphatehydrolysis of the reactive substancesStage I (Reactions 1-5) Consumption of 2 ATPsStage II (Reaction 6-10) Generation of 4 ATPsRecycling of NAD+ Homolactic fermentation under anaerobiccondition in muscle: reduction of pyruvate tolactate by NADH Alcoholic fermentation under anaerobiccondition in yeast: decarboxylation of pyruvate toCO2 and acetaldehyde (and its subsequentreduction to ethanol by NADH) Aerobic oxidation: mitochondrial oxidation ofeach NADH to NAD+ yields three ATPsHexokinase (HK)Phosphoglucose isomerase (PGI)Mechanism of phosphoglucose isomerasealdoseketosePhosphofructokinase (PFK)Significant role in the control of glycolysisAldolaseBase-catalyzed retro aldol condensationTwo classes of aldolase Class I (animal and plants) Formation of thecovalent enzyme-substrate Schiff baseintermediate Class II (fungi, algae and some bacteria) Metal(Zn2+ or Fe2+) stabilizes the enolate intermediateEnzymatic mechanism of Class I aldolaseTriose phosphate isomerase (TIM)Transition state analog inhibitors of TIMProposed enzymatic mechanism of TIMFlexible loop closes over the active siteProtecting the enediol intermediate from hydrolysisTIM is a perfect enzyme Diffusion controlled reaction The interconversion of GAP and DHAP is atequilibriumK = [GAP]/[DHAP] = 4.73 x 10-2 As GAP is utilized in the succeeding reaction,more DHAP is converted to GAPSummary for the first stage of glycolysisGlycelaldehyde-3-phosphate dehydrogenase(GAPDH)Elucidating the enzymatic mechanism of GAPDHEnzymatic mechanism of GAPDHPhosphoglycerate kinase (PGK):The first ATP generationMechanism of the PGK reactionEnergetics of the GAPDH-PGK reaction pairGAP + Pi + NAD+ 1,3-BPG + NADH1,3-BPG + ADP 3PG + ATPGo'= +6.7 kJ/molGo'= -18.8 kJ/molGAP + Pi + NAD+ + ADP 3PG + NADH + ATPGo'= -12.1 kJ/molPhosphoglycerate mutase (PGM)Reaction primerReaction mechanism of PGMSynthesis and degradation of 2,3-BPG inerythrocytesLinkage between glycolysis and oxygen transport(2,3-BPG deficiency)(2,3-BPG accumulation)EnolaseThe mechanism of enolasePyruvate kinase: Second ATP generationMechanism of pyruvate kinaseSummary for the second stage of glycolysisMetabolic fate of pyruvateNAD+ regenerationby homolactic fermentation in muscleStereoselective reduction of pyruvateRecycling of lactateAlcoholic fermentation in yeastMechanism of pyruvate decarboxylaseRegeneration of NAD+ byalcohol dehydrogenase (ADH)Metabolic fate of ingested ethanolGasoholEnergetics of fermentationHomolactic fermentation (Energy efficiency: 31%)Glucose 2Lactate + 2H+ Go'= -196 kJ/mol(2 ATP generated: Go'= 61 kJ/mol)Alcohol fermentation (Energy efficiency: 26%)Glucose 2Ethanol + 2CO2 Go'= -235 kJ/mol(2 ATP generated: Go'= 61 kJ/mol)Glycolysis is used for rapid ATP production Number of ATP produced Glycolysis : 2 ATP per glucose Oxidative phosphorylation: 38 ATP perglucose The rate of ATP production by anaerobicglycolysis can be up to 100 times fasterthan that of oxidative phosphorylationATP production in fast and slow-twitch muscle fibers(Predominant in musclescapable of short bursts of rapid activity)Nearly devoid of mitochondria Production of ATP almost exclusivelyby anaerobic fermentation(Predominant in musclesfor slow and steady contracton)Rich in mitochondria Production of ATP almost exclusivelythrough oxidative phosphorylationControl of glycolysisNonequilibriumreactions(possible fluxcontrol points)Effectors of the nonequlibrium enzymes ofglycolysisPhosphofructokinase isthe major flux-controlling enzyme of glycolysisInhibitor site ATP allosterically inhibits PFK bybinding to the T state AMP, ADP and F2,6P allostericallyactivates PFK by binding to the RstateActive siteInhibitor siteActive siteT R conformational change of PFKT stateR stateInhibits R T transitionRepulsionSalt bridgeAMP overcomes the ATP inhibition of PFK Adenylate kinase catalyzes the reaction:2ADP ATP + AMPK=[ATP][AMP][ADP]2= 0.44 In muscle, [ATP]50[AMP] and [ATP] 10[ADP] 10% Decrease in [ATP] result in 100% increasein [ADP] and >400% increase in [AMP] Effect on PFK is amplifiedSubstrate cycling in the regulation of PFKFructose-1,6bisphosphatase(FBPase)(G = -8.6 kJ/mol)PFK(G = -25.9 kJ/mol)In resting muscleIn active muscleMetabolism of hexoses other than glucoseThe metabolism of fructoseThe metabolism of galactoseThe metabolism of mannose...
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- Spring '09