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Chapter 14

Chapter 14. Chem 341 Suroviec Fall 2013. 8 reactions Oxidizes acetyl group of Acetyl CoA to 2 CO 2. I. Citric Cycle Overview. I. General Features. Circular Pathway oxidizes acetyl groups from many sources. Net reaction. In eukaryotes all enzymes of CAC are located in mitochondria

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Chapter 14

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  1. Chapter 14 Chem 341 Suroviec Fall 2013

  2. 8 reactions Oxidizes acetyl group of Acetyl CoA to 2 CO2 I. Citric Cycle Overview

  3. I. General Features • Circular Pathway oxidizes acetyl groups from many sources • Net reaction • In eukaryotes all enzymes of CAC are located in mitochondria • 1 CO2 produced in 1 round of the cycle • Oxidation of acetyl groups to 2 CO2 requires transfer of 4 pair of electrons

  4. II. Synthesis of Acetyl CoA • Pyruvate Dehydrogenase: Multienzyme Complex • Group of non covalently associated enzymes that catalyze 2+ sequential steps in metabolic pathway • Formed from pyruvate through oxidative decarboxylation • Pyruvate dehydrogenase (E1) • Dihydrolipoyl transacetylase (E2) • Dihydrolipoyl dehydrogenase (E3) • 24 E2 proteins associated as trimers at the corners of cube • 24 E1 proteins form dimers that associate with E2 core along the 12 edges. • The 12 E3 proteins form dimers that attach to the 6 faces of E2 cube • c) Combining a) and b) forms a 60 subunit complex

  5. B. Pyruvate Dehydrogenase Overall Reaction • Pyruvate dehydrogenase (E1) • A TPP requiring enzyme • TPP acts as electron sink in the reaction

  6. Hydroxyethyl group transferred to E2 Lipoamide uses lysine Cyclic disulfide reversibly reduced 2. Lipoamide

  7. Yields acetyl CoA and dihydrolipoamide-E2 3. E2 transesterification 4. Regenerate E2 • E3 becomes reduced • Regenerates E2 • Disulfide interchange reaction

  8. Reoxidize E3 5. Reoxidize E3

  9. III. Enzymes of CAC • Citrate synthase • Aconitase • Isocitrate dehydrogenase • a-ketoglutarate dehydrogenase: • Succinyl CoA synthetase • Succinate dehydrogenase • Fumerase • Malate dehydrogenase

  10. Citrate Synthase Catalyzes the condensation of acetyl-CoA and oxaloacetate Free enzyme is a dimer Active site closes when oxaloacetate binds Conformational changes seals oxaloacetate in binding site and shuts out the solvent III. Enzymes of the CAC

  11. Catalyzes reversible isomerization of citrate to isocitrate B. Aconitase C. NAD+ Dependant Isocitrate Dehydrogenase • Catalyzes oxidative decarboxylation of isocitrate to a-ketogluterate

  12. Catalyzes oxidative decarboxylation of a-ketogluterate Is a multienzyme complex E1: a-ketoglutarate dehydrogenase E2: dihydrolipoyl transsuccinylase E3: dihydrolipoyl dehydrogenase D. a-ketoglutarate dehydrogenase E. Succinyl-CoA Synthetase • Cleaves “high-energy” succinyl-CoA to synthesis of GTP • Reaction almost energy neutral.

  13. Catalyzes stereospecific dehydrogenation of succinate to fumerate Inhibited by malonate F. Succinate Dehydrogenase

  14. Regeneration of oxaloacetate G. Fumerase H. Malate dehydrogenase • Catalyzes the hydration of double bond of fumarate to form malate

  15. IV. Regulation of CAC • Availibity of substrates • Need for CAC intermediates • Demand for ATP

  16. A. Regulation of pyruvate decarboxylation • Product inhibition by NADH and acetyl-CoA • NADH, acetyl-CoA compete with NAD+ and CoA for binding sites • Drive with E2 and E3 • Covalent modification by phosphorylation/dephosphorylation of E1

  17. B. Rate-Controlling Enzymes • Same method as in glycolysis • Flux of metabolites through the CAC is proportional to the rate of cellular oxygen consumption • 3 main mechanisms • Substrate availability • Product inhibition • Competitive feedback inhibition

  18. B. Rate-Controlling Enzymes • Regulators are acetyl-CoA, oxaloacetate, NADH • Flux varies with substrate concentration

  19. V. Pathways that use CAC intermediates • Glucose biosynthesis • Fatty acid synthesis • Amino Acid synthesis

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