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BC368: Biochemistry of the Cell II Citric Acid Cycle Chapter 16 March 12, 2015 3 stages of respiration Production of acetyl-CoA (e.g., during glycolysis and the bridging reaction) Oxidation of acetyl-CoA via the citric acid cycle Electon transport and oxidative phosphorylation to produce lots of ATP Fig 16-1 Mitochondrial Architecture Glycolysis takes place in the cytosol The citric acid cycle takes place in the mitochondrial matrix The Bridging Reaction H+ + The Bridging Reaction Fig 16-2 The Bridging Reaction E1: orange E2: green E3: yellow Pyruvate dehydrogenase complex 1. Decarboxylation 3. Acetyl group to CoA 2. Oxidation 4. Restore enzyme Fig 16-6 Fig 16-6 Pyruvate dehydrogenase complex Step 1. Decarboxylation Fig 16-6 Fig 16-6 Step 1: Decarboxylation TPP is derived from vitamin B1 Common for decarboxylation reactions Carries carbon groups transiently Fig 14-15 Pyruvate dehydrogenase complex Step 2. Oxidation, with reduction of E2 Fig 16-6 Fig 16-6 Step 2: Oxidation Hydroxyethyl group is oxidized to acetyl group, transferred to lipoamide of E2, which is reduced. Lipoic Acid “Swinging Arm” Swinging arm acyl group carrier Transfers intermediates between different enzyme sites of interest here The Marsh Test Pyruvate dehydrogenase complex Step 3. Transfer to CoA Fig 16-6 Fig 16-6 Step 3: Transfer to CoA Acetyl group is transferred to coenzyme A by E2. Coenzyme A Derived from Vitamin B5 (pantothenic acid) “Activates” the acetyl group Fig 16-3 Pyruvate dehydrogenase complex Step 4. Restoring the enzyme Fig 16-6 Fig 16-6 Step 4: Restoring the enzyme FAD of E3 reoxidizes dihydrolipoamide. NAD+ reoxidizes FADH2. Fig 16-6 FAD/FADH2 Derived from Vitamin B2 (riboflavin) 1 or 2 electron acceptor NAD+/NADH Derived from Vitamin B3 (niacin) 2 electron acceptor Pyruvate dehydrogenase complex Fig 16-6 Fig 16-6 Coenzyme A Acetyl group is activated in two ways: Carbonyl carbon is activated for attack by nucleophiles Methyl carbon is more acidic Fig 16-3 The Citric Acid Cycle Reaction 1: Condensation Citrate synthase mechanism 1. deprotonation of methyl group of acetyl-CoA Fig 16-9 Citrate synthase mechanism 2. enolate attacks carbonyl of OA, forming citroyl-CoA Fig 16-9 Citrate synthase mechanism 3. hydrolysis of thioester releases citrate and CoA Fig 16-9 Reaction 2: Isomerization A symmetric molecule that acts asymmetric! Chemically, these carbons are identical! A symmetric molecule that acts asymmetric! Chemically, these carbons are identical! So both these products should be formed A symmetric molecule that acts asymmetric! Chemically, these carbons are identical! So both these products should be formed Prochiral molecules can act chiral! Reaction 3: Oxidative Decarboxylation Reaction 4: Oxidative Decarboxylation Reaction 5: Substrate-level phosphorylation Succinyl-CoA synthetase reaction Hydrolysis of CoA-SH drives phosphorylation of succinate within the enzyme-substrate complex Succinate transfers its phosphate group to the enzyme Enzyme phosphorylates GDP Reactions 6, 7, and 8 Oxidation Hydration Oxidation Summary of TCA Fig 16-14 Regulation Irreversible reactions are regulated In general, energy charge is key: AMP/NAD+ activate ATP/NADH inhibit Product inhibition Fig 16-19 Anaplerotic Reactions Fig 16-16 Anaplerotic Reactions Example: pyruvate carboxylase, which uses a biotin (vitamin B7) cofactor to carry CO2 Case Study Daniel plans to enter the Mr. Colby contest and wants to get jacked. He has begun adding raw eggs to his diet and is up to a dozen a day. Unfortunately, he has been experiencing lactic acidosis during his weight training and hypoglycemia between meals. What’s up with Daniel? Case Study KD ≈ 10-15 M Pyruvate carboxylase Carboxyl group of bicarbonate is “activated” by phosphorylation Pyruvate carboxylase “Activated” CO2 is passed to biotin cofactor with loss of Pi Pyruvate carboxylase CO2 is passed to second active site for rxn with pyruvate Pyruvate carboxylase CO2 is released for reaction with pyruvate to form OA. Glyoxylate cycle Plants and some microorganisms can convert acetyl-CoA to oxaloacetate for net gain of carbon and net synthesis of TCA intermediates Fig 16-22 Intersection with TCA Glyxoylate pathway runs simultaneously with TCA but in a different compartment. Fig 16-24 Coordinated regulation Isocitrate is a branch point; its fate depends on relative activities of isocitrate dehydrogenase (TCA) and isocitrate lyase (glyoxylate cycle). Fig 16-25 Case Study Vania can’t believe that she feels so lousy. Even though it is St. Patrick’s Day weekend and she’s been up all night partying, she’s never felt this bad before. Her head is pounding, and she feels tired, weak, dizzy, and sick to her stomach. She would drink some water, but she lost her Nalgene bottle last week somewhere, and the walk to the dining hall is just way too far. 1. What is wrong with Vania? 2. What are the consequences of dehydration on metabolism? 3. What are the metabolic breakdown products of ethanol? 4. What role do these metabolic products play in the citric acid cycle? 5. What would you recommend to Vania?