13.the citric acid cycle

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13.the citric acid cycle

• 1. the citric acid cycle
  • 1.1. aka Krebs cycle, tricarboxylic acid cycle(TCA)
  • 1.2. oxidizes acetyl CoA to CO2
  • 1.3. produces ATP(GTP)/NADH/FADH2
  • 1.4. NADH/FADH2 then go on to make more ATP in electron transport and oxidative phosphorylation
• 2. conversion of pyruvate to acetyl CoA
  • 2.1. pyruvate dehydrogenase links glycolysis to the citric acid cycle
  • 2.2. oxidative decarboxylation: pyruvate + HS-CoA +NAD+ →(pyruvate dehydrogenase complex)→ acetyl-CoA + CO2 + NADH
  • 2.3. pyruvate must enter the mitochondria to enter the TCA cycle
  • 2.4. pyruvate dehydrogenase complex
    • E1: pyruvate dehydrogenase
      • cofactor: TPP
      • catalyze: oxidative decarboxylation of pyruvate
      • ①carbanion of TPP + pyruvate + 2H+ → hydroxyethyl-TPP +CO2
      • ②hydroxyethyl-TPP + lipoamide → carbanion of TPP + acetyllipoamide
    • E2: dihydrolipoamide acetyltransferase
      • cofactor: lipoamide
      • catalyze: transfer the acetyl group to Co-A
      • ③Coenzyme-A + acetyllipoamide → acetyl CoA + dihydrolipoamide
    • E3: dihydrolipoamide dehydrogenase
      • cofacter: FAD
      • catalyze: turn the reduced lipoamide to oxidized
      • ④dihydrolipoamide + FAD → lipoamide + FADH2
      • ⑤FADH2 + NAD+ → FAD + NADH + H+
  • 2.5. pyruvate(3C) → acetyl-CoA(2C) + CO2
• 3. the citric acid cycle oxidizes acetyl CoA
  • 3.1. two general features
    • the flow of carbon
    • the production of "high energy" molecules
• 4. the citric acid cycle enzyme
  • 4.1. condensation
    • acetyl-CoA + oxaloacetate + H2O →(citrate synthase)→ citrate + CoA-SH
    • 2C + 4C = 6C, irreversible
  • 4.2. dehydration & hydration
    • ①citrate ←(aconitase)→ H2O + cis-aconitate
    • ②cis-aconitate ←(aconitase)→ H2O + isocitrate
    • 6C = 6C
  • 4.3. oxidative decarboxylation
    • ①isocitrate + NAD+/NADP+ →(isocitrate dehydrogenase)→ oxalosuccinate + NADH/NADPH + H+
    • ②oxalosuccinate → α-ketoglutrate + CO2
    • 6C = 5C + CO2, the first oxidation-reduction reactions, irreversible
  • 4.4. oxidative decarboxylation
    • α-ketoglutrate + CoA-SH + NAD+ →(α-ketoglutrate dehydrogenase complex)→ succinyl-CoA + CO2 + NADH
    • 5C = 4C + CO2, the second oxidation-reduction reactions, irreversible
  • 4.5. substrate-level phosphorylation
    • succinyl-CoA + GDP + Pi →(succinyl-CoA synthetase)→ succinate + GTP + CoA-SH
    • succinyl-CoA synthetase: two isozymes, one for GDP, the other for ADP
    • 4C = 4C, the only substrate-level phosphorylation
  • 4.6. dehydrogenation
    • succinate + FAD ←(succinate dehydrogenase)→ fumerate + FADH2
    • succinate dehydrogenase: the only membrane-bound
    • 4C = 4C, the third oxidation-reduction reactions
    • add: NADH electronic(transport per O2, 10H+); FADH2(transport per O2, 6H+)
  • 4.7. hydration
    • fumarate + OH- ←(fumarase)→ carbanion transition state
    • carbanion transition state + H+ ←(fumarase)→ L-malate
    • 4C = 4C
  • 4.8. dehydrogenation
    • L-malate + NAD+ ←(malate dehydrogenase)→ oxaloacetate + NADH + H+
    • 4C = 4C, the fourth oxidation-reduction reactions
  • 4.9. total
    • produces 1GTP(ATP), 2CO2, 4 reduced coenzymes(1FADH2 + 3NADH)
• 5. entry of pyruvate into mitochondria
• 6. reduced coenzymes can fuel the production of ATP
  • 6.1. all the NADH + FADH2 will eventually pass their electrons to O2 after being transferred through a series of electron carriers
  • 6.2. the complete oxidation of each NADH molecule leads to the generation of about 2.5ATP, and FADH2 of about 1.5ATP
  • 6.3. the energy of TCA cycle
  • 6.4. the energy of glycolysis + TCA cycle
    • 2glyceraldehyde 3-phosphate → 2 1,3-bisphosphoglycerate
      • NADH → FADH2: glycerol 3-phosphate shuttle, 1.5
      • NADH → NADH: malate-asparat shuttle, 2.5
    • the total energy: 30/32
  • 6.5. add: the mechanism used to shuttle NADH equivalents from the cytosol to the mitochondrial matrix
    • glycerol 3-phosphate shuttle
    • malate-aspartate shuttle
• 7. regulation of the citric acid cycle
  • 7.1. the four enzymes to regulate
    • ①pyruvate dehydrogenase complex
    • ②citrate synthase
    • ③isocitrate dehydrogenase
    • ④α-ketoglutarate dehydrogenase
    • when ADP/ATP or NAD+/NADH RATIO is high, the TCA cycle is turned on
  • 7.2. the regulation of pyruvate dehydrogenase complex
    • allosteric regulation
      • inhibit by Acetyl-CoA(E2)
      • inhibit by NADH(E3)
    • covalent modification(mammalian, E1)
      • phosphorylation: inactive
      • dephosphorylation: active
• 8. the citric acid cycle isn't always a "cycle"
  • 8.1. amphibolic: anobolic pathway + catabolic pathway
  • 8.2. anaplerotic reactions
    • pyruvate carboxylase: pyruvate → oxaloacetate(animal)
    • PEP carboxykinase: PEP → oxaloacetate(animal)
    • PEP carboxylase: PEP → oxaloacetate(bacteia&plant)
    • malic enzyme: pyruvate → malate
• 9. the glyoxylate pathway
  • 9.1. plants + some bacteria use glyoxylate cycle to produce 4-C compounds from acetyl-CoA
  • 9.2. isocitrate lyase and malate synthase are the short-circuiting enzymes
  • 9.3. the glyoxylate pathway
    • ①acetyl-CoA → citrate → isocitrate →(isocitrate lysase)→ glyoxylate + succinate
    • ②glycoxylate →(malate synthase)→ malate → oxlaoacetate
    • total: 2acetyl-CoA + NAD+ +2H2O → succinate + 2CoA + NADH + H+
  • 9.4. the relationship between the TCA and the glyoxylate pathway
    • fatty acids(lipid body) → fatty acids(glyoxysome) → succinate(glyoxysome) → succinate(mitochondrion) → malate(mitochondrion) → malate(cytosol) → oxaloacetate → gluconeogenesis