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Pyruvate Dehydrogenase Complex and Tricarboxylic Acid-cycle May 12, 2014 Hagop Atamian [email protected] Recall from Glycolysis • Glycolysis is the first step of aerobic cellular respiration. • The end product of glycolysis is pyruvate . • Glycolysis takes place in the cytosol where all the enzymes are present. of cells • Pyruvate enters the mitochondrion to be metabolized further. Mitochondrial Compartments Pyruvate Dehydrogenase Complex • Pyruvate dehydrogenase is a large complex containing many copies of each of three enzymes: – Pyruvate Dehydrogenase (PDH) – Dihydrolipoyl Transacetylase (DALT) – Dihydrolipoyl Dehydrogenase (DLD) • Has five cofactors: – TPP Catalytic – Lipoic acid – FAD – NAD+ – CoA-SH Oxidative Decarboxylation of Pyruvate O CH3 C NADH + H+ NAD+ CO2 O C O- Pyruvate dehydrogenase complex O Pyruvate CH3 C S CoA Acetyl CoA CoA-SH Decarboxylation O CH3 C O 2e-‐ -‐ Oxidation CH3 C + Oxidative Decarboxylation of Pyruvate Pyruvate Dehydrogenase Complex • Pyruvate dehydrogenase is a large complex containing many copies of each of three enzymes: – Pyruvate Dehydrogenase (PDH) – Dihydrolipoyl Transacetylase (DALT) – Dihydrolipoyl Dehydrogenase (DLD) • Has five cofactors: – TPP Catalytic – Lipoic acid – FAD – NAD+ – CoA-SH What is the Net Result of PDHc Reactions? Pyruvate + CoA + NAD+——> CO2 + acetyl-CoA + NADH + H+ Acetyl CoA: A Common Meeting Point • Acetyl-CoA is an important molecule in metabolism. • In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). O CH3 C S CoA • Several metabolic pathways converge to Acetyl-CoA including: 1. Fatty acid metabolism 2. Amino acid metabolism 3. Carbohydrate metabolism Acetyl CoA: A Common Meeting Point synthesis of the neurotransmitter acetylcholine Tricarboxylic Acid Cycle (TCA-cycle) • Also known as citric acid cycle and Krebs cycle. Hans Adolf Krebs (1900-‐1981) Nobel Prize in Medicine (1953), which he shared with Fritz Lipmann. h$p://en.wikipedia.org/wiki/Hans_Adolf_Krebs TCA-cycle • Harvests chemical energy from biological fuel in the form of electrons in NADH and FADH2. • Consists of a series of eight reactions. • Converts acetyl-CoA to two CO2 while conserving the free energy for ATP production. – The energy is stored as: three NADHs, one FADH2, and one GTP. • Intermediates from the TCA-cycle can be used to synthesize molecules such as amino acids and fatty acids. Summary • The final product of glycolysis is pyruvate. It is located in the cytosol . • In order to enter the TCA-cycle pyruvate has to be oxidized to Acetyl-CoA, converted acetyl-CoA releasing C02. pyruvatedehydrogenase dehydrogenase complex • This is achieved by pyruvate complex (PDHc) (PDHc), which consists of three three enzymes and is located in the mitochondrial matrix. mitochondrial matrix • use inner mitochondrial membrane is impermeable. Summary • The primary function of the TCA-cycle is oxidation of acetyl CoA to two CO2. acetyl CoA • The energy from these oxidation reactions is captured as: 1. NADH NADH 2. FADH2 FADH2 • e. TCA-cycle in Detail Total of eight reactions Reaction 1: Condensation Reaction CoA-SH O CH3 C S CoA + O- Acetyl CoA O O C 1 C 2 * O CH2 3 C 4 O- Oxaloacetate Citrate Synthase H 2O Citrate O- O O O- C CH2 C1 C * OH O CH2 3 C 4 O∆G°’ = -‐32.2 kJ/mol Reaction 2: Rearrangement Reaction O- O O O- C CH2 C1 C * O CH2 3 O- C 4 Citrate OH Aconitas e O- O C O O- C1 OH O CH2 CH * CH 3 C 4 O- Isocitrate ∆G°’ = 13.3 kJ/mol Reaction 3: First Oxidative decarboxylation CO2 O C NAD+ O O- OC1 OH O CH2 CH 2 CH 3 C 4 O- Isocitrate dehydrogenase O O- C CH2 CH2 2 O O C 3 C 4 O- NADH + H+ Isocitrate The only irreversible reaction. α-ketaglutarate ∆G°’ = -‐20.9 kJ/mol Reaction 4: Second Oxidative Decarboxylation CO2 O O- C CH2 CH2 2 O O C 3 C 4 O- α-ketaglutarate Back to four carbon molecule α-ketaglutarate dehydrogenase NAD+ NADH + H+ ∆G°’ = -‐33.5 kJ/mol O O- C O CH2 CH2 2 C 3 S CoA Succinyl CoA Reaction 5: Oxidation Reaction O O- C CoA-SH O CH2 CH2 2 C 3 S CoA Succinyl CoA Succinyl CoA synthetase GDP O O- C GTP O CH2 CH2 2 C 3 O- Succinate ∆G°’ = -‐2.9 kJ/mol Summary • In terms of carbons: A two carbon acetyl group has been linked to oxaloacetate and two CO2 molecules have been liberated. • In terms of energy captured: Two NAD+ have been reduced to NADH + H+. One ATP produced. Leaving us with a molecule of succinate Reaction 6: Oxidation Reaction O O- C Alkane CH2 CH2 2 O C 3 O- Succinate Dehydrogenase (membrane bound) O O- C Alkene CH CH 2 Succinate FAD FADH2 O C 3 O- Fumarate ∆G°’ = 0 kJ/mol Reaction 7: Hydration Reaction O O- C O CH H2O O- CH 2 C 3 O- Fumarate Fumarase O OH C CH H O CH 2 C 3 Malate O∆G°’ = -‐3.8 kJ/mol Reaction 8: Final Oxidation Reaction Regeneration of Oxaloacetate O- O OH C CH H O CH 2 C 3 Malate O- Malate dehydrogenase NAD+ O- O O H C C CH 2 O C 3 O- NADH + H+ Oxaloacetate ∆G°’ = 29.7 kJ/mol Regenerated VS Starting Oxaloacetate O- O- O O H C C CH 2 O O C 1 C 2 O O- C 3 Oxaloacetate O CH2 3 C 4 O- Oxaloacetate Review of the TCA-cycle Acetyl CoA Citrate Synthase NADH Malate dehydrogenase OAA Citrate Aconitase Malate Isocitrate Fumarase Isocitrate dehydrogenase NADH & CO2 Fumarate FA Succinate DH dehydrogenase 2 α-Ketaglutarate α-Ketaglutarate dehydrogenase GTP Succinyl Succinate CoA NADH & CO2 Succinyl CoA syhthetase h$p://tru-‐wealth.blogspot.com/2013/05/your-‐bodys-‐chemistry-‐pyruvate-‐for.html TCA-cycle: In Terms of Carbon # of the Different Steps h$p://www.uic.edu/classes/bios/bios100/summer2002/lect10.htm What’s Next • We saw how the acetyl-CoA made from glucose, fat, or protein burnt and energy captured as NADH and FADH2. • Next lecture we will see how this captured energy is used to make ATP via oxidative phosphorylation. THE END More questions?? Please email me @ [email protected]