Glycolysis
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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

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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


Glycolysis

  • 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


Glycolysis

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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