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GLUCOSE METABOLISM

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Glucose 2 pyruvate 2 ATP. Pathway common in all organisms-10 common enzymes. Also known as the 'Embden-Meyerhof-Parnas Pathway' after researchers from the 1940's ... – PowerPoint PPT presentation

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Title: GLUCOSE METABOLISM


1
Chapter 14
  • GLUCOSE METABOLISM

2
OVERVIEW OF GLYCOLYSIS
  • Key energy-production pathway
  • Glucose? 2 pyruvate 2 ATP
  • Pathway common in all organisms-10 common enzymes
  • Also known as the Embden-Meyerhof-Parnas
    Pathway after researchers from the 1940s

3
OVERVIEW OF GLYCOLYSIS
  • Glucose2NAD2ADP 2 Pi?2pyruvate2NADH2ATP
  • Stage 1 energy investment rxns 1-5 consumes 2
    ATP
  • Stage 2 energy recovery rxns 6-10 generates 4
    ATP and 2 NADH
  • NET 2 ATP and 2 NADH

4
OVERVIEW OF GLYCOLYSIS
  • PATHWAY Figure 14.1

5
REACTIONS OF GLYCOLYSIS
  • Enzyme 1 Hexokinase
  • Glucose ATP Mg2 ? Glucose-6-P ADP
  • Mg is essential for shielding ?, ?, and/or ?
    phosphate charges during nucleophilic attack of P
    by Glucose
  • Substrate binding closes enzyme active cleft,
    excluding water, moving ATP nearer to glucose
    molecule (catalysis by proximity effect) and
    expediting the nucleophilic reaction

6
REACTIONS OF GLYCOLYSIS
  • Enzyme 2 Phosphoglucose Isomerase (PGI)
  • Glucose-6-P ? Fructose-6-P
  • Aldose (pyranose) to Ketose (furanose) with ring
    opening and reclosing
  • Classic acid-base enzyme catalysis mechanism
    involving a Lys-H donor and Glu-H acceptor
    (Figure 14.3)

7
REACTIONS OF GLYCOLYSIS
  • Enzyme 3 Phosphofructokinase (PFK)
  • Fructose-6-P ATP Mg2 ? Fructose-1-6-BisP
  • Bis versus Di because PO4 not attached to each
    other
  • Mechanism very similar to hexokinase
    nucleophilic attack of Mg2-shielded ATP
  • Key control point (later - AMP, ATP, Citrate)

8
REACTIONS OF GLYCOLYSIS
  • Enzyme 4 Aldolase
  • Fructose-1-6-BisP ? G3P DHAP
  • Glucose atoms 1-3 3, 2, 1 of DHAP Glucose
    atoms 4-6 1, 2, and 3 of G3P
  • Aldol cleavage requirements (C2 carbonyl and C4
    hydroxyl) makes clear the need for the
    aldose-ketose isomerization
  • Enzyme shows diversity in mechanism. Many have
    Schiff base (sugar keto carbon amine) (covalent
    catalysis) intermediates (fig 14-5) or metal ion
    catalysis

9
REACTIONS OF GLYCOLYSIS
  • Enzyme 5 Triosphosphate Isomerase (TPI or
    TIM)
  • DHAP ? G3P
  • Enediol intermediate for isomerization
  • Acid-base catalysis like other isomerase, using
    Glu and His
  • Stereoelectronic control prevents C3-phosphate
    elimination, which would be favored product in
    non-enzymatic reaction
  • Perfect Enzyme rate is diffusion limited
  • Equilibrium favors DHAP coupled rxns with
    following steps keep conversion to C3P moving
    forward

10
REACTIONS OF GLYCOLYSIS
  • Enzyme 6 Glyceraldehyde-3-Phosphate
    Dehydrogenase (GAPDH)
  • G3P NAD Pi ? 1,3 BPG NADH H
  • Aldehyde oxidation (exergonic) drives synthesis
    of high-energy acyl phosphate (high-energy cpd)
  • Cys forms covalent intermediate, thiohemiacetal,
    which is oxidized to a thioester
  • Net Rxn is endergonic

11
REACTIONS OF GLYCOLYSIS
  • Enzyme 7 Phosphoglycerokinase (PGK)
  • 1,3 BPG ADP Mg2 ? 3-PG ATP
  • Substrate binding cleft swings closed after
    substrate binding to provide a water-free
    environment (proximity effect like hexokinase)
  • Couples with G3PDH to pull that reaction forward
  • Substrate level phosphorelation directly yields 1
    ATP

12
REACTIONS OF GLYCOLYSIS
  • Enzyme 8 Phosphoglycerate Mutase (PGM)
  • 3PG ? 2PG
  • Phosphorelated His on enzyme catalyzes the
    isomeration (proximity effect)
  • 2,3 BPG intermediate occasionally diffuses off
    the enzyme this is the factor that binds
    deoxyhemoglobin to lower its binding affinity but
    the majority of cpd produced in RBCs using
    separate enzyme

13
REACTIONS OF GLYCOLYSIS
  • Enzyme 9 Enolase
  • 2PG ? PEP H2O
  • Hydrolysis to form second high energy
    intermediate
  • Metal Ion Catalysis

14
REACTIONS OF GLYCOLYSIS
  • Enzyme 10 Pyruvate Kinase (PK)
  • PEP ADP ? Pyruvate ATP
  • Hydrolysis and tautomerization of second high
    energy intermediate
  • Requires both K and 2 Mg2 for ADP nucleophilic
    attack of PEP
  • Enolase Rxn was, thus, required to provide high
    energy compound capable of ATP generation

15
REACTIONS OF GLYCOLYSIS
  • SUMMARY
  • Energy investment in stage 1 recaptured in stage
    2
  • Products
  • ATP net 2 ATP/glucose
  • NADH 2 NADH/glucose to be regenerated by
    electron transport pathway with ATP production
  • PYRUVATE 2 pyruvates go to Citric Acid Cycle
    (aerobic) or lactate (anaerobic-regenerates NAD)
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