PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Lecture 17 - Chapters 18+19The Tricarboxylic Acid Cycle (TCA)a.k.a. Kreb’s cyclea.k.a. Citric Acid Cycle (CAC)Lecture 17 - Chapters 18+19The Tricarboxylic Acid Cycle (TCA)a.k.a. Kreb’s cyclea.k.a. Citric Acid Cycle (CAC)1OutlineOutline Overview of the process of complete oxidation of glucose (glycolysis + TCA Cycle + Oxidative Phophorylation) Preparatory step for TCA Cycle (Pyruvate Acetyl CoA) Reactions of the TCA Cycle (8) Regulation of the TCA Cycle TCA Cycle can also provide precursors for biosynthesis Anaplerotic reactions The glycoxylate cycle Overview of the process of complete oxidation of glucose (glycolysis + TCA Cycle + Oxidative Phophorylation) Preparatory step for TCA Cycle (Pyruvate Acetyl CoA) Reactions of the TCA Cycle (8) Regulation of the TCA Cycle TCA Cycle can also provide precursors for biosynthesis Anaplerotic reactions The glycoxylate cycle21x1x2x2x2x2x2x2x2x2x2x2x2x2x2x2xOxidative phosphorylationOxidative phosphorylationGTP/NADH3 NADH1 FADH234pyruvatePyruvate + CoA + NAD+ Acetyl CoA + CO2 + NADH + H+ Pyruvate + CoA + NAD+ Acetyl CoA + CO2 + NADH + H+ The Decisive Step - The Pyruvate Dehydrogenase ComplexThe Decisive Step - The Pyruvate Dehydrogenase Complex5Preparation for the cycleThe point of no returnPreparation for the cycleThe point of no return67Pyruvate Dehydrogenase Complex uses three Catalytic Coenzymes (Prosthetic groups)Pyruvate Dehydrogenase Complex uses three Catalytic Coenzymes (Prosthetic groups)FADFADThiamine pyrophosphate(TPP)Thiamine pyrophosphate(TPP)Lipoic acidLipoic acidE1E2E3Thiazole ring8Lipoic Acid + Lysine = LipoamideLipoic Acid + Lysine = Lipoamide9Pyruvate Dehydrogenase Complex uses two Stoichiometric CoenzymesPyruvate Dehydrogenase Complex uses two Stoichiometric CoenzymesNAD+NAD+ATPATPPantothenic acidPantothenic acid-mercaptoethalamine-mercaptoethalamineCoenzyme A(Bound to acetyl group)Coenzyme A(Bound to acetyl group)10E2E2E1E3PDH Catalytic and Stoichiometric CoenzymesPDH Catalytic and Stoichiometric CoenzymeslipoamideNAD+CoA11The synthesis of acetyl CoA from pyruvate consists of three steps:The synthesis of acetyl CoA from pyruvate consists of three steps:1 1 2 2 3312Step 1: Decarboxylation (E1)Step 1: Decarboxylation (E1)13Step 2. Oxidation (E1):Step 2. Oxidation (E1):Acetyl group is oxidized and transferred to one of lipoamide “S”. The other “S” of lipoamide is reduced.Acetyl group is oxidized and transferred to one of lipoamide “S”. The other “S” of lipoamide is reduced.14Step 3. Formation of acetyl CoA (E2):Step 3. Formation of acetyl CoA (E2):154. Reoxidation of dihydrolipoamide (E3)4. Reoxidation of dihydrolipoamide (E3)165. Transfer of electrons to NAD+ (E3)5. Transfer of electrons to NAD+ (E3)17http://iai.asm.org/content/28/3.toFlexible Linkages Allows Lipoamide to move between Active SitesFlexible Linkages Allows Lipoamide to move between Active Sites18High blood glucose+ Low energy chargeHigh blood glucose+ Low energy chargeLow blood glucose+ High energy chargeLow blood glucose+ High energy chargeRegulation of the PDH ComplexRegulation of the PDH Complex19Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3 NAD+ NAD+Acetyl CoAAcetyl CoAPyruvatePyruvateNADHNADHAllosteric Regulation of E2 and E3Allosteric Regulation of E2 and E3Acetyl CoANADHSubstratesSubstratesATPATPPyruvateCoANAD+ProductsProducts20The Covalent Regulation of the Pyruvate Dehydrogenase Component (E1) in Higher EukaryotesThe Covalent Regulation of the Pyruvate Dehydrogenase Component (E1) in Higher EukaryotesE1E1E1E121Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3activePyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3inactiveP-ATPATPADPADPPiPiH2OH2OPyruvate dehydrogenase kinasePyruvate dehydrogenase kinasePyruvate dehydrogenase phosphatasePyruvate dehydrogenase phosphatase22Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3activePyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3inactiveP-ATPATPADPADPPiPiH2OH2ONAD+, HS-CoA, ADP, PyruvateNAD+, HS-CoA, ADP, PyruvatePyruvate dehydrogenase kinasePyruvate dehydrogenase kinasePyruvate dehydrogenase phosphatasePyruvate dehydrogenase phosphataseNADH, Acetyl CoANADH, Acetyl CoAHigh energy stimulates kinaseNAD+, Ca2+ and HS-CoANAD+, Ca2+ and HS-CoALow energy stimulates phosphataseinsulin (liver and adiposeepinephrineinsulin (liver and adiposeepinephrine23Advantages of Multienzyme ComplexesAdvantages of Multienzyme Complexes-Can pass substrate/intermediate quickly and efficiently,(faster reaction and less side product)- Component assembled in best stoichiometry-Can pass substrate/intermediate quickly and efficiently,(faster reaction and less side product)- Component assembled in best stoichiometry24The TCA cycleThe TCA cycle3 NADH1 FADH225Two Phases of TCATwo Phases of TCAPhase 1Phase 1Phase 2Phase 226TCA ReactionsTCA ReactionsReaction 1: Condensation (2+4=6)Reaction 2: Dehydration-RehydrationReaction 3: DecarboxylationReaction 4: DecarboxylationReaction 5: Substrate-level PhosphorylationReaction 6: OxidationReaction 7: HydrationReaction 8: Oxidation TCA provide a chemically feasible way of cleaving a two-carbon compoundCH3COO- CO2 + CO2TCA provide a chemically feasible way of cleaving a two-carbon compoundCH3COO- CO2 + CO2First StageFirst StageSecond StageSecond Stage27ΔG° = -31.4 kJ/mol, ′ΔG′ = -53.9 kJ/mol ΔG° = -31.4 kJ/mol, ′ΔG′ = -53.9 kJ/molCitrate Synthase forms citrate from oxaloacetate and acetyl coenzyme ACitrate Synthase forms citrate from oxaloacetate and acetyl coenzyme AError in p. 332 of textbook:Used citrate instead of OAA Error in p. 332 of textbook:Used citrate instead of OAA 28The mechanism of citrate synthase prevents undesirable reactionsThe mechanism of citrate synthase prevents undesirable reactions29Reaction 2 -Citrate is isomerized into isocitrateReaction 2 -Citrate is isomerized into isocitrateΔG° = +6.7 kJ/′ molΔG° = +6.7 kJ/′ molAconitaseAconitase30TCA Cycle: Steps 3-4 Elimination of 2 Cs from Acetyl CoA TCA
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