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  1. E1: Pyruvate decarboxylase Coenzyme
    Thiamine pyrophosphate (TPP)
  2. E2: dihydrolipoyl transacetylase Coenzyme is
    • Lipoic acid
    • CoA
  3. E3: dihydrolipoyl dehydrogenase Coenzymes
    • FAD
    • NAD
  4. Pyruvate
    • Endproduct of aerobic glycolysis
    • must be transported back to mitochondria before it can enter TCA cycle by a transporter that helps it cross the mito. membrane
    • in the matrix; pyruvate turns into Acetyl CoA by pyr. Dehydrogenase complex.
    • If elevated, E1 will be 100% active
  5. Pyruvate Dehydrogenase complex
    • not part of TCA proper
    • source of acetyl CoA
    • 2 carbon substrate
    • Has the 3 E's
  6. E1 (PDH) Pyr-dyhrogen-complex
    • kinase phosphorylates and inhibits E1
    • Phosphatase dephosphorylates and activates E1
    • The Kinase is allosterically activated by ATP,Acetyl CoA, and NADH.
    • calcium activates PDH phosphatase which stimulates E1
    • pyruvate inhibits kinase; therefore E1 goes up.
  7. Potent inhibitor of PDH kinase
  8. skeletal muscle releases
    CA2+ during contraction stimulates PDH complex = energy production
  9. beginning of respiration
    • transfer of pyruvate to matrix of mito.
    • transfer of coA to pyruvate; makes acetyl CoA
    • release of co2
    • form nadh
  10. Each glucose makes 2 pyruvate
    1glucose= 2NADH+2acetyl CoA + 2co2
  11. slide 6: Catabolism
    • Nadp+ to nadph
    • reduced substrate to oxidized product
  12. slide 6: Anabolism
    • Nadph to Nadp+
    • oxidized precursor to reduced product.
  13. Pyruvate dehydrogenase
    • in the mitochondria
    • converts pyruvate to acetyl CoA
    • CoA is needed for citrate production ( citrate- 1st substrate in the tca cycle)
    • makes 3 enzyme complexes E1,2,3.
    • Coenzymes needed for activation
  14. Pyruvate dehydrogenase deficiency 
    (4x4 card 19)
    • disruption of mitocondria
    • neuro degenerative disorders
    • sex-linked(effects both M&F) or autosomal dominant defect.
    • neonatal death
    • weakness, Nervous system defects, lactic acidosis.
    • high lactate and pyruvate
    • Treatment: PDH enzyme, restriction of carbs and givin TPP may reduce symptoms.
  15. Arsenic toxicity
    • interfere with glycolysis
    • inhibits pdh, the complex that needs lipoic acid as cofactor.
    • mixes with SH group of lipoic acid making Cofactor unavailable from pdh
    • effects CNS(brain), neurological problems
    • rash on foot and skin
    • treatment: chelating agents(binds to metal making it inactive)
    • treatment: anti lewsite, or bal(2,3dimercatopropanol)
  16. slide 7: TCA (tricarboxylic acid cycle)
    • also known as citric acid or kerb's cycle
    • energy producing pathway
    • food turns to the cycle as acetyl CoA and oxidized to CO2 producing coenzymes & GTP
    • Starts with 4carbon oxaloacetate, adds 2C from acetyl CoA, loses 2C as CO2, regenerates 4C oxaloacetate.
    • Electrons transferred by cycle to NAD & FAD
    • Electrons go to O2 by Electron transport chain, and ATP is made by oxidative phosphorylation.
    • ATP also made from GTP, by sub-level phospho.
  17. slide 8: Cristae location
    inside the mitochondria (intermembrane space)
  18. Succinate dehydrogenase (inner membrane)
    all ezymes in citric acid cycle are in the matrix or inner membrane which are in all cells except mature RBC's and platelets.
  19. TCA cycle regulation
    • regulated by 3 enzymes
    • 1. Citrate synthase
    • 2. isocitrate dehydrogenase
    • 3. alpha ketoglutarate dehydrogenase
    • They are activated/inhibited by different metabolites.
    • they control flow of substrates due to need of atp
  20. Citrate synthase
    • inhibited by ATP, NADH, succinyl CoA.
    • Stimulated by insulin
  21. Isocitrate dehydrogenase
    • the cycle's "Pacemaker"
    • stimulated by ADP
    • inhibited by ATP & NADH

  22. @-Ketoglutarate dehydrogenase
    • Inhibited by 2 of it's products ( NADH & succinyl CoA)
    • Also inhibited by ATP & GTP
  23. slide 12: 1st step of TCA
    • Acetyl CoA condenses to Citrate
    • enzyme: citrate synthase
    • Cleavage of thioster bond in Ac-CoA gives energy
    • Citrate: the product is an inhibitor of this rxn
  24. 2nd step of TCA
    • citrate is isomorized(transformed) to isocitrate
    • Aconitate is enzyme intermediate
    • enzyme: aconitase
    • Equilibrium of rxn favors citrate.
  25. Slide14: 3rd step - regulative step
    • Isocitrate oxidized to alpha-ketoglutarate - in 1st oxidateive decarbox- rxn.
    • CO2 produced
    • Electrons are passed to NAD to form NadH & H+
  26. regulatory step-
    Enzyme: Isocitrate dehydrogenase
    • regulatory enzyme of TCA cycle
    • Allosterically activated by ADP
    • Inhibited by NADH
  27. Malfunction of TCA (Fluoroacetate)
    • A poison, converts to fluorocitrate and inhibits Aconitase
    • blocks the cycle and its energy output
  28. Deficiency of these vitamins impairs cycle
    • Niacin -->NAD
    • Riboflavin (vit b2) -->FAD
    • Thiamine (vit B1) --> thiamine¬† pyrophosphate. Also in alcoholics - effects CNS
    • Vit b12 (cobalamin) --> succ CoA
  29. What happens to NADH & FADH2
    8 nadh & 2fadh2 feed into electron transport chain.
  30. citric acid cycle and gluconeogenesis
    • cit acid cycle accepts metabolites, contributes to intermediates for use in anabolic pathway like gluconeogen.
    • Carbons entering as Acet-CoA always turn to Co2, never contribute C to gluconeogen.
    • Acet-CoA is not a substrate of gluconeogen.
    • C from AA and pyruvate convert to malate, then exported to cytosol, then converted to oxaloacetate to enter gluconeo-pathway.
  31. Total ATP produced by citric acid cycle
    24 ATP/acet-CoA oxidized

    2 Acet-CoA per glucose

    • 3nadh->3nad = 9ATP
    • Fadh2->fad= 2atp
    • GDP +p1-> GTP = 1
    • Total ATP: 12
  32. 9.1 needed for conversion of pyruvate to acetyl CoA and CO2
    lipoic acid
  33. 9.2 condition that decreases (oxidation-combine with 02) of acetyl CoA
    low Nad/NadH ratio
  34. 9.3 A+B+FAD+H2O --> C+FADH2+Nadh
    what is ABC?
    • A. succinate
    • B. NAD
    • C. oxaloacetate
  35. 9.4
    1Mo old, has abnormal CNS, lactic acidosis, low thiamine pyrophosphate (1x10-4mM) tpp normal at 5%, and 80% normal activity on high (.4mM) of TPP.
    What do you administer?
    admin. thiamine will reduce his serum lactate conc. and improve his symptoms.
Card Set
Tricarboxylic Acid Cycle (TCA)
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