Chemistry 153A-3825/06Handout #4•Bioenergetics/Metabolism (Chapter 13)•Glycolysis (Chapter 14)Topics CoveredexergonicendergonicGeneral features:Anabolic versus Catabolic pathwaysAnabolic pathways. Start from similar precursorscompounds which are built into cellular componentsby a divergent set of pathways.Catabolic pathways. Start from a diverse array of energy rich compounds which are metabolized through a similar pathway to produce energy.Overview of catabolicpathways(1) Glycolysis(2) Citric Acid Cycle(3) Electron transfer & oxidative phosphorylationGlucose is oxidized to CO2. Some of the energy of oxidation is directly harnessed as chemicalenergy in the form of ATP.Most of the energy ofoxidation is eventuallyharnessed as chemical energy by transferringe- to carriers (NADH, FADH2), followed by transfer of e- to O2ATPATP!!!!!Glucose + 6O26CO2+ 6H2OΔG’o= -686 kcal/moleGlycolysis -> Citric Acid Cycle -> Oxidative PhosphorylationA fraction of this free energy will beharvested as chemical energy in theform of ATP Catabolic pathways: The oxidation of glucoseto produce chemical energy in the form ofATP (Adenosine triphosphate)24 electrons are ultimately transferred fromGlucose to O2.Why Adenosine triphosphate (ATP)??Energy Currency:(1) Hydrolysis yields a significant amount free energy-7.3 kcal/moleThermodynamics of ATP Hydrolysis: reviewHydrolysis of ATP Favorable. Energy is releasedWhy are the hydrolysis products (ADP+Pi) more stable than the reactants (ATP)?(1) More resonance forms per phosphate in hydrolysis productsATPADPPi(2) Charge separation in products(3) Better solvation of productsATP is kinetically stable. ATP in water does not readilyget converted to ADP and Pi. Enzymes are needed tocatalyze the hydrolysis reaction.Slow reaction“High-energy” phosphorylated compounds:Compounds that release a lot of free energy when they transfer their phosphate groups to water. X-P + H2O X + PiATP the universal energy carrier.It releases a significant amount of free energy upon hydrolysis.But not too much so it can be a conduit between “high energy”phosphate donors and low energy acceptors.CytosolMitochondriaEukaryotic CellGLYCOLYSISCitric Acid CycleOxidative PhosphorylationPOverview of catabolic Reactions in the cellPhosphorylated glycolyticintermediates are stuckin the cytosol+ H++ 2H++ H+Preparatory PhaseReaction #1HexokinaseKinase: Enzyme that transfers a phosphoryl group between ATP and a metabolite (or protein)Glucose + ATP Glucose-6-P + ADP + H+(a transferase)αβγ(-4 kcal/mol)OH2106Induced fit of the Hexokinase active site enables itto discriminate water from glucoseBinding of glucose correctly assembles the active site for catalysisRelative reaction rate1Relative reaction rateReaction #2PhosphoglucoseIsomerase(an isomerase)Glucose-6-P Fructose-6-P(0.4 kcal/mol)General MechanismCis-enediol intermediateAldose/Ketose conversionReaction #3Phosphofructokinase(a transferase)Fructose-6-P + ATP Fructose-1,6-P + ADP + H+Similar to reaction #1Key regulatory step(-3.4 kcal/mol)+Dihydroxyacetone phosphateReaction #4Fructose-1,6-PGlyceraldehyde-3-PAldolaseGeneral Mechanism (aldol cleavage)(5.7 kcal/mol)(a lyase)Class 1 AldolaseMaking the Schiff base**Triose Phosphate IsomeraseDihydroxyacetonephosphateGlyceraldehyde3-phosphateReaction #5(DHAP)(GAP)Ketose/Aldose isomerization (similar to reaction #2)(1.8 kcal/mol)2 ATP + Glucose2 ADP + 2H+ + 2 GAPH+H+2XRunning Tally of the Preparatory PhaseH+The Payoff!Reaction #6(1.5 kcal/mol)(a oxidoreductase)Nicotinamide adenine dinucleotide: a hydride ion carrierNADHNAD++ H++ 2e-NADHHydride ionNAD+(catabolic reactions)(anabolic reactions)Coupling favorable oxidation of an aldehydeto the formation of an acyl phosphateEnergy from favorable oxidation is stored in a transient enzyme-substrate acyl thioester bond.Energy from favorable enzyme-substrate acyl thioester bondis stored in the acyl phosphate bond of the productReaction #6ExampleHydrolysis of thioester bonds liberate a lot of free energyReaction #7Substrate Level Phosphorylation: Direct transfer of a phosphoryl group from a “high-energy” phosphate donor(1,3-Bisphosphoglycerate) to ADP.Substrate Channeling. Some of the enzymes of the glycolyticpathway are loosely associated with each other in the cytosol because they are highly concentrated. This enables some of the intermediates to be channeled from one enzyme to the next.The advantages of substrate channelingReaction #8Phosphoglycerate MutaseReaction #9Dehydration does not significantly change the chemical energy. ΔG’o= 1.8 kcal/mole = G’oproducts - G’osubstratesBut it redistributes energy, creating a better phosphate donorPi PiH2OH2O-4.2 kcal/mole-14.8 kcal/molePhosphoenol pyruvate has enough free energy to drive the formation of ATP in thenext step.1.8 kcal/molReaction #10tautomerizationSubstrate-level phosphorylation of ATPH+(-7.5 kcal/mol)Net Reaction of GlycolysisReactions #1-5Reactions #6-10(7)The Catabolic Fate of Pyruvate under Aerobic and Anaerobic ConditionsNAD+ (required)NADH -> NAD+NADH -> NAD+NADH -> NAD+Aerobic RespirationLactic AcidFermentationAlcoholFermentationLactic AcidFermentationBack to step #6 of glycolysisTransport to liver where itis recycled as glucoseGlucose + 2ADP +2Pi 2 ATP + 2H2O + 2 LactateNet Reaction of glycolysis + Lactic Acid FermentationDerived from niacinAlcohol FermentationSimilar to lactic acid fermentationGlucose + 2ADP +2Pi 2 ATP + 2H2O + 2 Ethanol + 2CO2Net Reaction of glycolysis + Alcohol FermentationDerived from vitamin B1Repeatedly used to cleave bonds next to carbonyl groupsTPPGlycogenGlycolysisGluconeogenesisLactate(anaerobic)Pentose PhosphatePathway(produces NADPHand ribose 5-phosphate)The big pictureCitric acid cycle(aerobic)Pentose Phosphate Pathway(a) Produces NADPH, a reducing agent needed for anabolic reactions.(b) Pentose type sugars. Required for the production nucleic acids Pentose Phosphate PathwayGlycolysisGlycogenBreakdownRegulatedGlucoseGlycogenGlucoseGlycogenBreakdownGlycogenSynthesisGlycogen SynthesisRegulated!Chapter 20. Figure 20-12You do not need to know mechanism or detailsGluconeogenesis:Synthesis of glucose from non-hexosePrecursors (lactate, fatty acids and amino acids)Chapter 20. Figure 20-2lactateGlycogenGluconeogenesisPentose Phosphate PathwayGlycolysis: Regulated at Branch points R : Enzymes that Regulated in GlycolysisRRRB CΔG < 0Rate-limiting steps: reactions in the pathway that
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