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Citric Acid Cycle

Citric Acid Cycle. Gylcolysis. Electron Transport and Oxidative phosphorylation. TCA Cycle. The TCA Cycle. (aka Citric Acid Cycle, Krebs Cycle) Pyruvate (actually acetate) from glycolysis is degraded to CO 2 Some ATP is produced More NADH is made

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Citric Acid Cycle

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  1. Citric Acid Cycle

  2. Gylcolysis Electron Transport and Oxidative phosphorylation TCA Cycle

  3. The TCA Cycle • (aka Citric Acid Cycle, Krebs Cycle) • Pyruvate (actually acetate) from glycolysis is degraded to CO2 • Some ATP is produced • More NADH is made • NADH goes on to make more ATP in electron transport and oxidative phosphorylation

  4. Entry into the TCA Cycle • Pyruvate is translocated from the cytosol to the mitochondria • Pyruvate is oxidatively decarboxylated to form acetyl-CoA • Pyruvate dehydrogenase uses TPP, CoASH, lipoic acid, FAD and NAD+ • Acetyl-CoA then enters TCA cycle thru citrate synthase

  5. Pyruvate Dehydrogenase Complex Composed of three enzymes: • pyruvate dehydrogenase (E1) (cofactor = TPP) • Dihydrolipoamide acetyltransferase (E2) (cofactor = Lipoamide, CoA) • Dihydrolipoamide dehydrogenase (E3) (cofactor = FAD, NAD+)

  6. Pyruvate Dehydrogenase

  7. Citrate Synthase • Only step in TCA cycle that involves the formation of a C-C bond

  8. Aconitase • Isomerization of Citrate to Isocitrate • Citrate is a poor substrate for oxidation • So aconitase isomerizes citrate to yield isocitrate which has a secondary-OH, which can be oxidized • Aconitase uses an iron-sulfur cluster to position citrate (binds –OH and carboxyl of central carbon)

  9. Isocitrate Dehydrogenase • Oxidative decarboxylation of isocitrate to yield  -ketoglutarate • Classic NAD+ chemistry (hydride removal) followed by a decarboxylation • Isocitrate dehydrogenase is a link to the electron transport pathway because it makes NADH • Rxn is metabolically irreversible

  10.  -Ketoglutarate Dehydrogenase • A second oxidative decarboxylation • This enzyme is nearly identical to pyruvate dehydrogenase - structurally and mechanistically • Five coenzymes used - TPP, CoASH, Lipoic acid, NAD+, FAD

  11. Succinyl-CoA Synthetase • A substrate-level phosphorylation • A nucleoside triphosphate is made (ATP in plants/bacteria and GTP in animals) • Its synthesis is driven by hydrolysis of a CoA ester

  12. Succinate Dehydrogenase • An oxidation involving FAD • Mechanism involves hydride removal by FAD and a deprotonation • This enzyme is actually part of the electron transport pathway in the inner mitochondrial membrane • The electrons transferred from succinate to FAD (to form FADH2) are passed directly to ubiquinone (UQ) in the electron transport pathway • Enzyme inhibited by malonate

  13. Fumarase • Hydration across the double bond • trans-addition of the elements of water across the double bond • Stereospecific reaction

  14. Malate Dehydrogenase • An NAD+-dependent oxidation • The carbon that gets oxidized is the one that received the-OH in the previous reaction • This reaction is energetically expensive • Go' = +30 kJ/mol

  15. Reduced Coenzymes Fuel ATP Production • Acetyl-CoA + 3 NAD+ + Q + GDP + Pi +2 H20  HS-CoA + 3NADH + QH2 + GTP + 2 CO2 + 2 H+ • Isocitrate Dehydrogenase 1 NADH=2.5 ATP • a-ketoglutarate dehydrogenase 1 NADH=2.5 ATP • Succinyl-CoA synthetase 1 GTP=1 ATP • Sunccinate dehydrogenase 1 QH2=1.5 ATP • Malate Dehydrogenase 1 NADH=2.5 ATP • Total of 10 ATPs gained from oxidation of 1 Acetyl-CoA

  16. Regulation of TCA Cycle

  17. TCA Cycle provides intermediates for many biosynthetic processes

  18. The Anaplerotic Reactions • The "filling up" reactions • PEP carboxylase - converts PEP to oxaloacetate • Pyruvate carboxylase - converts pyruvate to oxaloacetate • Malic enzyme converts pyruvate into malate

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