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 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Lecture 17 (Ch. 18 & 19) – The Tricarboxylic Acid Cycle (TCA)a.k.a. Kreb’s cyclea.k.a. Citric Acid Cycle (CAC)1• 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 cycleOxidative phosphorylationGTP/NADH3 NADH1 FADH22Pyruvate + CoA + NAD+ Acetyl CoA + CO2 + NADH + H+ The Decisive Step - The Pyruvate Dehydrogenase Complex34Pyruvate Dehydrogenase Complex uses three Catalytic Coenzymes (Prosthetic groups)E3: FADE1: Thiamine pyrophosphae (TPP)E2: Lipoic acid5Lipoic Acid + Lysine = Lipoamide6lipoyllysinePyruvate Dehydrogenase Complex uses two Stoichiometric CoenzymesNAD+ADPPantothenic acid-mercaptoethalamineCoenzyme A(Bound to acetyl group)7The synthesis of acetyl CoA from pyruvate consists of three steps:8Step 1: Decarboxylation (E1)910Pyruvate dehydrogenaseStep 2. Oxidation (E1):Acetyl group is oxidized and transferred to one of lipoamide “S”. The other “S” of lipoamide is reduced.11Step 3. Formation of acetyl CoA (E2):1213Dihydrolipoyl transacetylase (E2) of PDC4. Reoxidation of dihydrolipoamide (E3)145. Transfer of electrons to NAD+ (E3)http://iai.asm.org/content/28/3.toFlexible Linkages Allows Lipoamide to move between Active Sites15High blood glucose+ Low energy chargeLow blood glucose+ High energy chargeRegulation of the PDH Complex16Allosteric Regulation of E2 and E3Products17NAD+Acetyl CoANADHSubstratesPyruvateAcetyl CoANADHATPThe Covalent Regulation of the Pyruvate Dehydrogenase Component (E1) in Higher EukaryotesE1 E118Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3P-ATP ADPPiH2OPyruvate dehydrogenase kinasePyruvate dehydrogenase phosphatase19active inactivePyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3activePyruvate dehydrogenase E1E2E3Pyruvate dehydrogenase E1E2E3inactiveP-ATP ADPPiH2OPyruvate dehydrogenase kinasePyruvate dehydrogenase phosphatase20NAD+, HS-CoA, ADP, PyruvateNADH, Acetyl CoAHigh energy stimulates kinaseNAD+, Ca2+ and HS-CoALow energy stimulates phosphataseinsulin (liver and adipose)epinephrineAdvantages of Multienzyme Complexes-Can pass substrate/intermediate quickly and efficiently,(faster reaction and less side product)- Component assembled in best stoichiometry21The TCA cycle3 NADH1 FADH222Two Phases of TCAPhase 1Phase 223TCA 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 + CO2First StageSecond Stage24ΔG° = -31.4 kJ/mol, ′ΔG′ = -53.9 kJ/molCitrate Synthase forms citrate from oxaloacetate and acetyl coenzyme A** Error in p. 332 of textbook: Used citrate instead of OAA 25OxaloacetateAcetyl CoA Citryl CoACitrate26Reaction 2 -Citrate is isomerized into isocitrateΔG° = +6.7 kJ/mol′Aconitase27Citrate cis-Aconitate Isocitrate28Two views of the reactionTCA Cycle: Steps 3-4 Elimination of 2 Cs from Acetyl CoA 293- Isocitrate is oxidized and decarboxylated to α-ketoglutarate ΔG° = -8.4 kJ/mol ′ ΔG′ = -17.5 kJ/mol Isocitrate Dehydrogenase30Isocitrate Oxalosuccinate -Ketoglutarate31Step 4Succinyl CoA is formed by the oxidative decarboxylation of α-ketoglutarateα-ketoglutarate dehydrogenase complex3233a.k.a. -Ketoglutarate34From last slideTCA Cycle: Steps 5-8 Regeneration of Oxaloacetate and Harvest of Energy-Rich Electrons35Reaction 5 - Succinyl CoA to SuccinateSuccinyl CoA synthetase36Substrate-level Phosphorylation by Succinyl CoA SynthetaseSuccinyl phosphatephosphohistidineSuccinyl CoAATP/GTPSuccinateADP/GDP37Oxaloacetate is regenerated Reactions 6-8Succinate DehydrogenasefumaraseMalate dehydrogenase38Succinate Fumarate MalateMalate Oxaloacetate39Succinate DehydrogenaseSuccinate Fumarate40FumaraseThe Net Reaction of the Citric Acid Cycle is:41Acetyl-CoA + 3 NAD+ + FAD + ADP + Pi + 2 H2O2 CO2 + 3 NADH + FADH2 + ATP + 2 H+ + CoAIsocitrateDehydrogenaseαKG DehydrogenaseFatty acid breakdownFatty acid synthesisRegulation of the TCA Cycle42Learn regulated enzymes in each pathwaysSubstrateProductAllosteric effectorPosttranscriptional modificationsLearn the products (ATP/NADH, CO2, etc.) of each pathway and the steps at which they are generated 43The Citric Acid Cycle is a Source of Biosynthetic Precursors44Anaplerotic “filling up” reactions45Pyruvate + CO2 + ATP + H2O oxoaloacetate + ADP + Pi + 2H+Two Phases of TCAPhase 1Phase 246The glycoxylate cycle enables plants and bacteria to convert fats into carbohydrates47•An anabolic variant of the TCA cycle – to make sugars in plants•Skips two decarboxylation steps (to make -KG and Succinyl CoA)•Uses 2 Acetyl CoA per cycle•Isocitrate Lyase makes Succinate and Glyoxylate•Allows some bacteria to grow on acetate as carbon sourceThe Glycoxylate Cycle484950Isocitrate Lyase5152Complete Oxidation of glucoseThe electrons from glucose oxidation feed into the electron transport pathway, driving synthesis of ATP.In mitochondiral
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