Citric Acid Cycle

Citric Acid Cycle - Chapter 21 Citric Acid Cycle The citric...

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Unformatted text preview: Chapter 21 Citric Acid Cycle The citric acid cycle is the “hub” of cellular metabolism Synthesis of Acetyl-CoA from pyruvate • Pyruvate dehydrogenase (PDH) multienzyme complex – Pyruvate dehydrogenase (E1) – Dihydrolipoyl transacetylase (E2) – Dihydrolipoyl dehydrogenase (E3) • E. coli PDH complex: ~ 4,600 kD (300Å) • Eukaryotic PDH complex: ~ 10,000 kD E. coli PDH multienzyme complex + E2 trimers at the 8 corners (24 E2) = E1 dimers along the 12 edges (24 E1) E3 dimers on the 6 faces (12 E3) 60-subunit complex Eukaryotic PDH complex The PDH complex requires five conenzymes Interconversion of lipoamide and dihydrolipoamide Architecture of the PDH complex The five reactions of the PDH complex The reaction of pyruvate dehydrogenase (E1) Transfer of the hydroxyethyl group to dihydrolipoyl transacetylase (E2) E2 catalyzes a transesterification reaction to generate an acetyl-CoA Regeneration of E2 by dihydrolipoyl dehydrogenase (E3) Reoxidation of the reduced E3 Catalytic reaction cycle of dihydrolipoyl dehydrogenase Regulation of pyruvate dehydrogenase • Inhibition: NADH, acetyl-CoA, ATP • Activation: NAD+, ADP, Ca2+ • Phosphorylation/dephosphorylation of the E1 subunit – Pyruvate dehydrogenase kinase – inactivates the E1 subunit – Pyruvate dehydrogenase phosphatase – activates the E1 subunit The citric acid cycle the Krebs cycle or the tricarboxylic acid (TCA) cycle • 3 NAD+ + FAD + GDP + Pi + Acetyl-CoA → 3 NADH + FADH + GTP + CoA + 2 CO2 • Oxidation of acetyl-CoA to 2 CO2 (4 electron pairs) while the reduction of 3 NAD+ (3 electron pairs) and FAD (1 electron pairs) • Occurs in mitochondria • Requires transport of substrates and products across the mitochondrial membrane from or to the cytoplasm • Intermediates are precursors for the biosynthesis of other compounds Citrate synthase Conformational changes in citrate synthase The open conformation The closed conformation Oxaloacetate Acetyl-CoA The mechanism of the citrate synthase reaction Aconitase The mechanism of the aconitase reaction Isocitrate dehydrogenase α-Ketoglutarate dehydrogenase complex Multienzyme complex • α-Ketoglutarate dehydrogenase (E1) – TPP • Dihydrolipoyl transsuccinylase (E2) – Lipoamide • Dihydrolipoyl dehydrogenase (E3) – FAD and NAD+ Succcinyl-CoA synthetase The mechanism of the succinyl-CoA reaction Succinate dehydrogenase (Competitive inhibitor) Fumarase Stereoselectivity of fumarase Not substrates Malate dehydrogenase The outcome of the citric acid cycle One glucose can yield 38 (?) ATPs under aerobic conditions via the citric acid cycle Rate-controlling enzymes of the citric acid cycle Regulation of the citric acid cycle The citric acid cycle is amphibolic (both anabolic and catabolic) • Cataplerotic reactions – reactions that utilize citric acid cycle intermediates – – – – Glucose biosynthesis: oxaloacetate Fatty acid biosynthesis: acetyl-CoA Amino acid biosynthesis: α-ketoglutarate and oxaloacetate Porphyrin biosynthesis: succinyl-CoA • Anaplerotic reactions – reactions that replenish citric acid cycle intermediates – Pyruvate carboxylase, PEP carboxykinase and PEP carboxylase: oxaloacetate – Malic enzyme: malate – Degradation of odd-chain fatty acids and certain amino acids: Succinyl-CoA – Amino acid degradation: α-ketoglutarate and oxaloacetate Anaplerotic reactions The citric acid cycle is amphibolic ...
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This note was uploaded on 10/16/2010 for the course CHEM 60280 taught by Professor Ryu during the Spring '09 term at TCU.

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