Lecture 17 Chapters 18 19 The Tricarboxylic Acid Cycle TCA a k a Kreb s cycle a k a Citric Acid Cycle CAC 1 Outline v Overview of the process of complete oxidaHon of glucose glycolysis TCA Cycle OxidaHve PhophorylaHon v Preparatory step for TCA Cycle Pyruvate Acetyl CoA v ReacHons of the TCA Cycle 8 v RegulaHon of the TCA Cycle v TCA Cycle can also provide precursors for biosynthesis v AnapleroHc reacHons v The glycoxylate cycle 2 1x 2x 2x 2x NADH 2x 2x 2x GTP OxidaHve phosphorylaHon 2x 3 NADH 1 FADH2 3 4 The Decisive Step The Pyruvate Dehydrogenase Complex Pyruvate CoA NAD Acetyl CoA CO2 NADH H pyruvate 5 PreparaHon for the cycle The point of no return 6 7 Pyruvate Dehydrogenase Complex uses three CatalyHc Coenzymes ProstheHc groups Thiamine pyrophosphate E1 TPP Thiazole ring E2 Lipoic acid E3 FAD 8 Lipoic Acid Lysine Lipoamide 9 Pyruvate Dehydrogenase Complex uses two Stoichiometric Coenzymes Coenzyme A mercaptoethalamine Bound to acetyl group Pantothenic acid NAD ATP 10 PDH CatalyHc and Stoichiometric Coenzymes NAD E1 E3 CoA lipoamide E2 E2 11 The synthesis of acetyl CoA from pyruvate consists of three steps 1 2 3 12 Step 1 DecarboxylaHon E1 13 Step 2 OxidaHon E1 Acetyl group is oxidized and transferred to one of lipoamide S The other S of lipoamide is reduced 14 Step 3 FormaHon of acetyl CoA E2 15 4 ReoxidaHon of dihydrolipoamide E3 16 5 Transfer of electrons to NAD E3 17 Flexible Linkages Allows Lipoamide to move between AcHve Sites h p iai asm org content 28 3 to 18 RegulaHon of the PDH Complex Low blood glucose High energy charge High blood glucose Low energy charge 19 Allosteric RegulaHon of E2 and E3 Pyruvate CoA NAD Substrates Pyruvate NAD Pyruvate dehydrogenase Acetyl CoA NADH Products E1 E2 E3 Acetyl CoA NADH ATP 20 The Covalent RegulaHon of the Pyruvate Dehydrogenase Component E1 in Higher Eukaryotes E1 E1 21 acHve ATP ADP inacHve Pyruvate Pyruvate dehydrogenase dehydrogenase E1 E1 Pyruvate dehydrogenase kinase E2 E2 Pyruvate dehydrogenase phosphatase E3 E3 P Pi H2O 22 NAD HS CoA ADP Pyruvate acHve ATP High energy sHmulates kinase NADH Acetyl CoA ADP inacHve Pyruvate Pyruvate dehydrogenase dehydrogenase E1 E1 Pyruvate dehydrogenase kinase E2 E2 Pyruvate dehydrogenase phosphatase E3 E3 P insulin liver and adipose epinephrine Pi H2O NAD Ca2 and HS CoA Low energy sHmulates phosphatase 23 Advantages of MulHenzyme Complexes Can pass substrate intermediate quickly and e ciently faster reacHon and less side product Component assembled in best stoichiometry 24 The TCA cycle 3 NADH 1 FADH2 25 Two Phases of TCA Phase 1 Phase 2 26 TCA ReacHons TCA provide a chemically feasible way of cleaving a two carbon compound CH3COO CO2 CO2 ReacHon 1 CondensaHon 2 4 6 ReacHon 2 DehydraHon RehydraHon ReacHon 3 DecarboxylaHon ReacHon 4 DecarboxylaHon ReacHon 5 Substrate level PhosphorylaHon ReacHon 6 OxidaHon ReacHon 7 HydraHon ReacHon 8 OxidaHon First Stage Second Stage 27 Citrate Synthase forms citrate from oxaloacetate and acetyl coenzyme A Error in p 332 of textbook Used citrate instead of OAA G 31 4 kJ mol G 53 9 kJ mol 28 The mechanism of citrate synthase prevents undesirable reacHons 29 ReacHon 2 Citrate is isomerized into isocitrate Aconitase G 6 7 kJ mol 30 TCA Cycle Steps 3 4 EliminaHon of 2 Cs from Acetyl CoA 31 3 Isocitrate is oxidized and decarboxylated to ketoglutarate Isocitrate Dehydrogenase G 8 4 kJ mol G 17 5 kJ mol 32 Step 4 Succinyl CoA is formed by the oxidaHve decarboxylaHon of ketoglutarate ketoglutarate dehydrogenase complex G 30 kJ mol G 43 9 kJ mol 33 TCA Cycle Steps 5 8 RegeneraHon of Oxaloacetate and Harvest of Energy Rich Electrons 34 ReacHon 5 Succinyl CoA to Succinate Succinyl CoA synthetase G 3 3 kJ mol G 0 35 Substrate level PhosphorylaHon by Succinyl CoA Synthetase Succinyl CoA Succinate Succinyl phosphate 1 2 Succinyl CoA synthetase ADP GDP ATP GTP phosphohisHdine 3 h p en wikipedia org wiki File Succinyl CoA Synthetase Mechanism Revised png 4 36 Oxaloacetate is regenerated ReacHons 6 8 Succinate Dehydrogenase fumarase Malate dehydrogenase 37 The Net ReacHon of the Citric Acid Cycle is 38 Fa y acid breakdown RegulaHon of the TCA Cycle Fa y acid synthesis Isocitrate Dehydrogenase KG Dehydrogenase 39 Learn regulated enzymes in each pathways Substrate Product Allosteric e ector Pos ranscripHonal modi caHons Learn the products ATP NADH CO2 etc of each pathway and the steps at which they are generated 40 The Citric Acid Cycle is a Source of BiosyntheHc Precursors 41 AnapleroHc lling up reacHons 42 Two phases of TCA Phase 1 Phase 2 43 The glycoxylate cycle enables plants and bacteria to convert fats into carbohydrates 44 The Glycoxylate Cycle 45 Complete OxidaHon of glucose The electrons from glucose oxidaHon feed into the electron transport pathway driving synthesis of ATP In mitochondiral matrix 46 Learning Goals Be able to list the coenzymes of the pyruvate dehydrogenase and the steps involved in the conversion of pyruvate to acetyl CoA Be able to recognize the intermediates and products of the citric acid cycle Understand how the pyruvate dehydrogenase complex and the citric acid cycle are regulated Know the roles of acetyl CoA and oxaloacetate Explain the di erences between the citric acid cycle and the glyoxylate cycle 47
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