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Glycolysis. Glucose → pyruvate (+ ATP, NADH) Preparatory phase + Payoff phase Enzymes Highly regulated (eg. PFK-1 inhibited by ATP) Form multi-enzyme complexes Pass products/substrates along: efficiency. Overall balance sheet. Glucose + 2NAD + + 2ADP + 2P i →

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glycolysis
Glycolysis
  • Glucose → pyruvate (+ ATP, NADH)
  • Preparatory phase + Payoff phase
  • Enzymes
    • Highly regulated (eg. PFK-1 inhibited by ATP)
    • Form multi-enzyme complexes
      • Pass products/substrates along: efficiency
overall balance sheet
Overall balance sheet

Glucose + 2NAD+ + 2ADP + 2Pi→

2 pyruvate + 2NADH + 2H+ + 2ATP + 2H2O

fermentation pathways alternate fate of pyruvate
Fermentation pathwaysAlternate fate of pyruvate
  • “Fermentation”: carbohydrate metabolism that generates ATP but doesn’t change oxidation state (no O2 used, no net change in NAD+/NADH)
  • Fermentation of pyruvate to lactate
    • Cells with no mitochondria (erythrocytes)
    • anerobic conditions
    • Regeneration of 2 NAD+ to sustain operation of glycolysis
    • No net change in oxidation state (glucose vs lactate)
  • Lactate is recycled to glucose (post-exercise)
fermentation pathways
Fermentation pathways
  • Fermentation of pyruvate to EtOH
    • Yeast and microorganisms
    • No net oxidation (glucose to ethanol)
    • EtOH and CO2 generated
aerobic respiration of glucose etc
Aerobic respiration of glucose (etc)
  • Glycolysis:
    • Start with glucose (6 carbon)
    • Generate some ATP, some NADH, pyruvate (2 x 3 carbon)
  • TCA cycle
    • Start with pyruvate
    • Generate acetate
    • Generate CO2 and reduced NADH and FADH2
  • Electron transport
    • Start with NADH/FADH2
    • Generate electrochemical H+ gradient
  • Oxidative phosphorylation
    • Start with H+ gradient and O2 (and ADP + Pi)
    • Generate ATP and H2O
aerobic respiration
Aerobic respiration
  • Stage 1:
    • Acetyl CoA production
      • Some ATP and reduced electron carriers (NADH)
      • Glycolysis (for glucose), pre-TCA
  • Stage 2:
    • Acetyl CoA oxidation
      • Some ATP, lots of reduced e- carriers (NADH/FADH2)
      • TCA cycle/Krebs cycle/Citric acid cycle
  • Stage 3:
    • Electron transfer and oxidative phosphorylation
      • Generate and use H+ electrochemical gradient
      • Use of reduced e- to generate ATP
fate of pyruvate under aerobic conditions tca cycle ch 16
Fate of pyruvate under aerobic conditions: TCA cycle (Ch. 16)
  • Oxidation of pyruvate in ‘pre-TCA cycle’
    • Generation of acetyl CoA (2 carbons)
    • CO2
    • NADH
  • Acetyl CoA → TCA cycle
    • Generation of ATP, NADH
pre tca cycle
Pre-TCA cycle
  • Pyruvate acetyl CoA
    • Via ‘pyruvate dehydrogenase complex’
      • 3 enzymes
      • 5 coenzymes
    • ~irreversible
    • 3 steps
      • Decarboxylation
      • Oxidation
      • Transfer of acetyl groups to CoA
  • Mitochondria
    • Transport of pyruvate
pre tca cycle1
Pre-TCA cycle
  • Coenzymes involved (vitamins)
    • Catalytic role
    • Thiamin pyrophosphate (TPP)
      • Thiamin
      • decarboxylation
    • Lipoic acid
      • 2 thiols disulfide formation
      • E- carrier and acyl carrier
    • FAD
      • Riboflavin
      • e- carrier
    • Stoichiometric role
    • CoA
      • Pantothenic acid
      • Thioester formation acyl carrier
    • NAD+
      • Niacin
      • e- carrier
pre tca cycle2
Pre-TCA cycle
  • Enzymes involved pyruvate dehydrogenase complex
    • multiprotein complex
    • Pyruvate dehydrogenase (24) (E1)
      • Bound TPP
    • Dihydrolipoyl transacetylase (60) (E2)
      • Bound lipoic acid
    • Dihydrolipoyl dehydrogenase (12) (E3)
      • Bound FAD
  • 2 regulatory proteins
    • Kinase and phosphatase
pre tca cycle3
Pre-TCA cycle
  • Step 1:
    • Catalyzed by pyruvate dehydrogenase
      • Decarboxylation using TPP
      • C1 is released
      • C2, C3 attached to TPP as hydroxyethyl
pre tca
Pre-TCA
  • Step 2
    • Hydroxyethyl TPP is oxidized to form acetyl linked-lipoamide
    • Lipoamide (S-S) is reduced in process
    • Catalyzed by pyruvate dehydrogenase (E1)
  • Step 3
    • Acetyl group is transferred to CoA
    • Oxidation energy (step 2) drives formation of thioester (acetyl CoA)
    • Catalyzed by dihydrolipoyl transacetylase (E2)
  • Step 4
    • Dihydrolipoamide is oxidized/regenerated to lipoamide
    • 2 e- transfer to FAD, then to NAD+
    • Catalyzed by dihydrolipoyl dehydrogenase (E3)
overall
Overall….
  • Pyruvate acetyl CoA
    • Via ‘pyruvate dehydrogenase complex’
    • 4 step process
      • Decarboxylation of pyruvate and link to TPP
      • Oxidation of hydroxyethyl TPP and reduction/acetylation of lipoamide
      • Transfer of acetyl group to CoA
      • Oxidation of lipoamide via FAD (and e- transfer to NAD+)
overall1
Overall….
  • Pyruvate acetyl CoA
    • Via ‘pyruvate dehydrogenase complex’
    • 4 step process
      • Decarboxylation of pyruvate and link to TPP
      • Oxidation of hydroxyethyl TPP and reduction/acetylation of lipoamide
      • Transfer of acetyl group to CoA
      • Oxidation of lipoamide via FAD (and e- transfer to NAD+)
pre tca1
Pre-TCA
  • Substrate channeling
    • Multi enzyme complex
    •  rxn rate
  • Facilitated by E2
    • ‘swinging’ lipoamide
    • accept e- and acetyl from E1 and transfer to E3
  • Pathology: mutations in complex/thiamin deficiency
regulation of pre tca
Regulation of pre-TCA
  • PDH complex
    • Inhibited by
      • Acetyl CoA, ATP, NADH, fatty acids
    • Activated by
      • CoA, AMP, NAD+
    • Phosphorylation
      • Serine in E1 phosphorylated by kinase
        • Inactive E1
        • Kinase activated by ATP, NADH, acetyl CoA…
      • Regulatory phosphatase hydrolyzes the phosphoryl
        • Activates E1
        • Ca2+ and insulin stimulate
tca cycle
TCA cycle
  • Aerobic process
    • “Generates” energy
    • Occurs in mitochondria
    • 8 step process
      • 4 are oxidations
      • Energy ‘conserved’ in formation of NADH and FADH2
        • Regenerated via oxidative phosphorylation
    • Acetyl group → 2 CO2
      • Not the C from the acetyl group
    • Oxaloacetate required in ‘catalytic’ amounts
    • Some intermediates
      • Other biological purposes
slide18

Step 1: condensation of oxaloacetate with acetyl CoA citrate

  • Via citrate synthase
    • Conformational change upon binding
    • Oxaloacetate binds 1st
      • Conf change to create acetyl CoA site
  • Citrate synthase
    • Conformational changes upon binding of oxaloacetate

TCA cycle

unbound

bound

slide19

TCA cycle

  • Mechanism of citrate synthase
  • 2 His and 1 Asp
  • 2 reactions
    • 1st rxn (condensation)
      • 2 steps
      • Highly unfavorable because of low oxaloacetate
    • 2nd rxn (hydrolysis)
      • Highly favorable because of thioester cleavage
      • Drives 1st rxn forward
  • CoA is recycled back to the pre TCA cycle
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