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Summary of the citric acid cycle

Summary of the citric acid cycle. For each acetyl CoA which enters the cycle: (1) Two molecules of CO 2 are released (2) Coenzymes NAD + and FAD (Q) are reduced (3) One GDP (or ADP) is phosphorylated (4) The initial acceptor molecule (oxaloacetate) is reformed

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Summary of the citric acid cycle

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  1. Summary of the citric acid cycle • For each acetyl CoA which enters the cycle: • (1) Two molecules of CO2 are released • (2) Coenzymes NAD+ and FAD (Q) are reduced • (3) One GDP (or ADP) is phosphorylated • (4) The initial acceptor molecule (oxaloacetate) is reformed • There are 8 reactions in the cycle. • Condensation – only rxn. that generates a C-C bond Enzyme: citrate synthase

  2. Binds substrates one at a time • Induced fit (conformational change) • Breaking high energy thioester bond makes -G Acid/Base catalysis

  3. Claisen condensation • Stabilization of intermediate • Release of product

  4. 2. Rearrangement –Elimination, then addition of H2O • Intermediate: C=C bond of cis-aconitate • Stereospecific • Reversible • Driven to completion by depletion of product by next rxn. in the cycle Enzyme: aconitase (aconitate hydratase)

  5. Oxidative decarboxylation • Metabolically irreversible • One of four oxidation-reduction reactions of the cycle • Hydride ion from the C-2 of isocitrate is transferred to NAD+ to form NADH • Oxalosuccinate is decarboxylated • Mn2+ stabilizes intermediate Enzyme: Isocitrate Dehydrogenase 2 forms – one uses NAD+; other uses NADP+

  6. Oxidative decarboxylation Enzyme: a-Ketoglutarate Dehydrogenase Complex Similar to pyruvate dehydrogenase complex (E3 is identical) Same coenzymes, identical mechanisms E1 - a-ketoglutarate dehydrogenase (with TPP) E2 - succinyltransferase (with flexible lipoamide prosthetic group) E3 - dihydrolipoamide dehydrogenase (with FAD)

  7. 5. Substrate level phosphorylation • Free energy in thioester bond of succinyl CoA is conserved as GTP (or ATP) Enzyme: Succinyl-CoA Synthetase • Dimer • One subunit specific for GTP or ATP • GTP and ATP are energetically equivalent GTP + ADP  GDP + ATP Enzyme: nucleoside diphosphate kinase G0 = 0 kJ/mol

  8. Dehydrogenation (oxidation) Enzyme: Succinate Dehydrogenase (SDH) Complex • Located on the inner mitochondrial membrane (plasma membrane in prokaryotes) • Dehydrogenation is stereospecific; only the trans isomer is formed • Complex of several polypeptides, an FAD prosthetic group and iron-sulfur clusters • Electrons are transferred from succinate to ubiquinone (Q), a lipid-soluble mobile carrier of reducing power • FADH2 generated is reoxidized by Q • QH2 is released as a mobile product (ETC)

  9. Substrate analog malonate is a competitive inhibitor of the SDH complex

  10. 7. Hydration • Stereospecific trans addition of water to the double bond of fumarate to form L-malate Enzyme: fumarase (fumarate hydratase)

  11. Oxidation Enzyme: L-malate dehydrogenase • Endergonic, but product constantly removed by highly exergonic rxn. #1 (citrate synthase) • [oxaloacetate] < 10-6 M (very low)

  12. Fates of carbon atoms in the cycle • Carbon atoms from acetyl CoA (red) are not lost in the first turn of the cycle

  13. Energy conservation by the cycle • Energy is conserved in the reduced coenzymes NADH, FADH2 (QH2) and one GTP (ATP) • Reduced coenzymes can be oxidized to produce ATP by oxidative phosphorylation (electron transport chain, ETC)

  14. Reduced Coenzymes Fuel the Production of ATP • Each acetyl CoA entering the cycle nets: • (1) 3 NADH • (2) 1 FADH2 (QH2) • (3) 1 GTP (or 1 ATP) • In ETC further oxidation yields: • 2.5 ATP per NADH • 1.5 ATP per FADH2 (QH2)

  15. Glucose degradation via glycolysis, citric acid cycle, and oxidative phosphorylation From 1 glucose  30-32 ATP

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