Lecture 17 Ch 18 19 The Tricarboxylic Acid Cycle TCA a k a Kreb s cycle a k a Citric Acid Cycle CAC 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 1 Oxidative phosphorylation NADH GTP 3 NADH 1 FADH2 2 The Decisive Step The Pyruvate Dehydrogenase Complex Pyruvate CoA NAD Acetyl CoA CO2 NADH H 3 4 Pyruvate Dehydrogenase Complex uses three Catalytic Coenzymes Prosthetic groups E1 Thiamine pyrophosphae TPP E2 Lipoic acid E3 FAD 5 Lipoic Acid Lysine Lipoamide lipoyllysine 6 Pyruvate Dehydrogenase Complex uses two Stoichiometric Coenzymes Coenzyme A mercaptoethalamine Bound to acetyl group Pantothenic acid NAD ADP 7 The synthesis of acetyl CoA from pyruvate consists of three steps 8 Step 1 Decarboxylation E1 9 Pyruvate dehydrogenase 10 Step 2 Oxidation E1 Acetyl group is oxidized and transferred to one of lipoamide S The other S of lipoamide is reduced 11 Step 3 Formation of acetyl CoA E2 12 Dihydrolipoyl transacetylase E2 of PDC 13 4 Reoxidation of dihydrolipoamide E3 5 Transfer of electrons to NAD E3 14 Flexible Linkages Allows Lipoamide to move between Active Sites http iai asm org content 28 3 to 15 Regulation of the PDH Complex Low blood glucose High energy charge High blood glucose Low energy charge 16 Allosteric Regulation of E2 and E3 Acetyl CoA NADH Products Substrates Pyruvate Acetyl CoA NADH NAD ATP 17 The Covalent Regulation of the Pyruvate Dehydrogenase Component E1 in Higher Eukaryotes E1 E1 18 active ATP ADP inactive Pyruvate dehydrogenase Pyruvate dehydrogenase P E1 E1 Pyruvate dehydrogenase kinase E2 Pyruvate dehydrogenase phosphatase E2 E3 E3 Pi H2 O 19 High energy stimulates kinase NADH Acetyl CoA NAD HS CoA ADP Pyruvate active ATP inactive ADP Pyruvate dehydrogenase Pyruvate dehydrogenase P E1 E1 Pyruvate dehydrogenase kinase E2 Pyruvate dehydrogenase phosphatase E3 E3 insulin liver and adipose epinephrine E2 Pi H2 O NAD Ca2 and HS CoA Low energy stimulates phosphatase 20 Advantages of Multienzyme Complexes Can pass substrate intermediate quickly and efficiently faster reaction and less side product Component assembled in best stoichiometry 21 The TCA cycle 3 NADH 1 FADH2 22 Two Phases of TCA Phase 1 Phase 2 23 TCA Reactions TCA provide a chemically feasible way of cleaving a two carbon compound CH3COO CO2 CO2 Reaction 1 Condensation 2 4 6 Reaction 2 Dehydration Rehydration First Stage Reaction 3 Decarboxylation Reaction 4 Decarboxylation Reaction 5 Substrate level Phosphorylation Reaction 6 Oxidation Reaction 7 Hydration Reaction 8 Oxidation Second Stage 24 Citrate Synthase forms citrate from oxaloacetate and acetyl coenzyme A Oxaloacetate Acetyl CoA Citryl CoA Citrate G 31 4 kJ mol G 53 9 kJ mol Error in p 332 of textbook Used citrate instead of OAA 25 26 Reaction 2 Citrate is isomerized into isocitrate Aconitase Citrate cis Aconitate Isocitrate G 6 7 kJ mol 27 Two views of the reaction 28 TCA Cycle Steps 3 4 Elimination of 2 Cs from Acetyl CoA 29 3 Isocitrate is oxidized and decarboxylated to ketoglutarate Isocitrate Dehydrogenase Isocitrate Oxalosuccinate Ketoglutarate G 8 4 kJ mol G 17 5 kJ mol 30 31 Step 4 Succinyl CoA is formed by the oxidative decarboxylation of ketoglutarate ketoglutarate dehydrogenase complex 32 a k a Ketoglutarate 33 From last slide 34 TCA Cycle Steps 5 8 Regeneration of Oxaloacetate and Harvest of Energy Rich Electrons 35 Reaction 5 Succinyl CoA to Succinate Succinyl CoA synthetase 36 Substrate level Phosphorylation by Succinyl CoA Synthetase Succinyl CoA ADP GDP Succinyl phosphate Succinate ATP GTP phosphohistidine 37 Oxaloacetate is regenerated Reactions 6 8 fumarase Succinate Dehydrogenase Succinate Fumarate Malate Malate dehydrogenase Malate Oxaloacetate 38 Succinate Dehydrogenase Succinate Fumarate 39 Fumarase 40 The Net Reaction of the Citric Acid Cycle is Acetyl CoA 3 NAD FAD ADP Pi 2 H2O 2 CO2 3 NADH FADH2 ATP 2 H CoA 41 Regulation of the TCA Cycle Fatty acid breakdown Fatty acid synthesis Isocitrate Dehydrogenase KG Dehydrogenase 42 Learn regulated enzymes in each pathways Substrate Product Allosteric effector Posttranscriptional modifications Learn the products ATP NADH CO2 etc of each pathway and the steps at which they are generated 43 The Citric Acid Cycle is a Source of Biosynthetic Precursors 44 Anaplerotic filling up reactions Pyruvate CO2 ATP H2O oxoaloacetate ADP Pi 2H 45 Two Phases of TCA Phase 1 Phase 2 46 The glycoxylate cycle enables plants and bacteria to convert fats into carbohydrates 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 source 47 The Glycoxylate Cycle 48 49 Isocitrate Lyase 50 51 52 Complete Oxidation of glucose In mitochondiral matrix The electrons from glucose oxidation feed into the electron transport pathway driving synthesis of ATP 53
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