1a Glucose Catabolism: Slides 1-53

Glycolysis, also known as Embden-Meyerhof-Parnas pathway
1. Located in cytosol
Sequence of 10 enzymatic reactions
1. 1 SIX-C molecule of glucose to 2 THREE-C molecule of pyruvate
  1. Generation of 2 ATP
  2. Net reaction: glucose + 2NAD+ + 2ADP + 2Pi → 2 pyruvate + 2NADH + 2ATP + 2H2O + 4H+
    1. Energy CONSUMPTION: 2 ATP used getting to 2 molecules of glyceraldehyde-3-phosphate from 1 molecule glucose
    2. Energy RECOVERY: 2 molecules glyceraldehyde-3-phosphate converted to 2 molecules pyruvate and generation of 4 ATP
2. [OTHER SLIDE SHOW] Control of Glycolysis: hexokinase, phosphofructokinase, pyruvate kinase
  1. 1. Hexokinase
    1. [other slide show]
  2. 2. PGI (Phosphoglucose Isomerase)
    1. Converts G6P to fructose-6-phosphate (F6P)
    2. Isomerization of aldose to ketose
    3. Reaction requires ring opening, isomerization and ring closure
  3. 3. PFK (Phosphofrucokinase)
    1. F6P phosphorylated to fructose-1,6-bisphosphate (Product is “bis” rather than “bi” because 2 phosphates not directly attached to each other)
      1. F6P + ATP → FBP + ADP + H+
    2. Phosphorylates similar to hexokinase
      1. Requires ATP and Mg+2 complex
    3. PFK central role pathway control - Allosteric enhancement by AMP ... Allosteric inhibition by ATP and citrate
  4. 4. Aldolase
    1. Catalyzes cleavage [aldol cleavage] of F1,6P (in half) to 2 trioses
      1. 1. glyceraldehyde-3-phosphate (GAP)
      2. 2. dihydroxyacetone phosphate (DHAP)
  5. 5. TIM (Triose phosphate isomerase)
    1. Triose phosphate isomerase (TIM) catalyzes the following
      1. 1. Interconversion of GAP and DHAP
        Interconversion so efficient that conc of 2 metabolites maintained at equilibrium conc
        [DHAP] » [GAP]
        GAP consumed by next step of glycolysis so DHAP converted to GAP to maintain equilibrium
        DHAP thus follows GAP into 2nd step of glycolysis, which allows single metabolite to enter 2nd step which is high-energy formation
      2. 2. A ketose to aldose
      3. Catalytically perfect enzyme
        Rate of bimolecular reaction between E and S diffusion is controlled
        P formed as rapidly as E and S collide
  6. 6. GAPDH (Glyceraldehyde-3-phosphate dehydrogenase)
    1. catalyzes the oxidation and phosphorylation of GAP by NAD+ and Pi to 1,3-bisphosphoglycerate (1,3-BPG) GAP + NAD+ + Pi ←→ 1,3-BPG + NADH + H+
      1. This is an aldehyde oxidation, an endergonic reaction (positive ΔG), being driven by the coupled reaction following this
        Endergonic reaction (requires energy for it to work)
  7. 7. PGK (Phosphoglycerate kinase)
    1. catalyzes reaction of 1,3-BPG and ADP forming ATP and 3-phosphoglycerate (3PG)
      1. Note: called a kinase because of the reverse reaction ATP + 3PG → 1,3-BPG and ADP
    2. Mg+2 required as cofactor for Mg+2-ATP complex
      1. Binding sites of Mg+2-ATP and 1,3-BPG on 2 different domains separated by ~ 10 Å; binding swings 2 domains together excluding water
    3. GAP + Pi + NAD+ + ADP → 3PG + NADH + ATP
      1. ΔG = -12.1 KJ/mol
      2. Example of substrate-level phosphorylation
      3. NADH routed thru electron transport yielding ATP
  8. 8. PGM (Phosphoglycerate mutase)
    1. catalyzes conversion of 3-phosphoglycerate to 2-phosphoglycerate
      1. Multistep process where: [1] E’s phosphoryl group (on His 8) transferred to 3-PG making 2,3-BPG [2] 2,3-BPG decomposes leaving phosphoryl group on E and product 2-PG
    2. Trace amounts of 2,3-bisphosphoglycerate (2,3-BPG) occasionally break away
      1. Available to “jump start” or regenerate phosphoenzyme
        2,3-bisphosphoglycerate also binds deoxy Hb decreasing Hb’s O2 affinity
        Consequently RBC’s require much more than trace amounts to prime inactive enzyme
        2,3-BPG is reversible in gluconeogenesis
  9. 9. Enolase
    1. catalyzes dehydration reaction of 2PG to phosphoenolpyruvate (PEP) + H2O
      1. Enzyme forms complex with cations, such as Mg+2 before substrate binds
      2. Creation of “high energy” phosphate
    2. Enolase is inhibited (blocking glycolysis) by F-
      1. In presence of Pi, F- forms complex with Mg+2 at enzyme’s active site, blocking S binding
  10. 10. Pyruvate kinase
    1. catalyzes: [1] Formation of pyruvate from PEP [2] Synthesis of ATP from ADP
      1. [1st step] Hydrolysis: release of high energy phosphate
      2. [2nd step] Tautomerization: conversion of “enol” pyruvate to “keto” pyruvate
        Releases more energy than 1st step
    2. Requires K+ and Mg+2
    3. Highly exergonic (releases energy) reaction providing enough energy for substrate level ATP synthesis
3 products of glycolysis
1. #1# ... 2 ATP: initial consumption of 2 ATP followed by production of 4 ATP
2. #2# ... 2 NAD+ converted to 2 NADH which is shunted into electron transport for ATP formation and regeneration of NAD+
3. #3# ... 2 molecules pyruvate which are still relatively reduced – enters TCA for complete oxidation to CO2 and synthesis of more ATP
Under anaerobic conditions, pyruvate metabolized to lesser extent to regenerate NAD+
Fermentation
1. Pyruvate has 3 metabolic fates depending on conditions
  1. Aerobic conditions – pyruvate completely oxidized to CO2 and H2O
  2. 2 different anaerobic conditions
    1. pyruvate converted to a reduced end product to oxidize the NADH produced by glyceraldehyde-3-phosphate dehydrogenase reaction
    2. in muscle: homolactic fermentation [dead end]
      1. pyruvate converted to lactate to regenerate NAD+
      2. During vigorous activity in muscle
      3. -Demand for ATP high -Supply of O2 low
      4. ATP synthesized anaerobically faster than aerobic oxidative phosphorylation
      5. Under these conditions
        Lactate dehydrogenase (LDH) catalyzes oxidation of pyruvate & NADH to lactate and NAD+
        Lactate burn is to keep up from committing suicide
        (pH dropped around hemoglobin → give up oxygen and force molecule into t-conformation (in r-conformation, would be able to pick up oxygen) → net overall effect is you create an environment in which hemoglobin does not bind oxygen → not able to transport oxygen to the tissue, which leads to death)
        2 acids created in anaerobic glycolysis
        If number of protons held constant, we can prevent burn from acid muscle burn
        Reaction freely reversible so pyruvate & lactate readily equilibrated
      6. Lactate represents dead end for anaerobic metabolism; lactate can either be: [a] Converted back to pyruvate or [b] Most carried (removed) to liver where used to synthesis glucose
        Lactate buildup does not cause muscle fatigue or soreness, but rather glycolytically generated acid H+
        Muscle can continue to work with high lactate if pH kept constant
      7. Overall reaction: Glucose + 2ADP + 2Pi → 2 lactate + 2ATP + 2H20 + 2H+
    3. in yeast: alcoholic fermentation
      1. pyruvate decarboxylated yielding CO2 and acetaldehyde which is then reduced by NADH yielding NAD+ and ethanol
        Anaerobic conditions in yeast
        Pyruvate converted to ethanol and CO2
        Enzyme decarboxylates pyruvate forming acetaldehyde and CO2
        Enzyme not found in animals
        Enzyme contains coenzyme thiamine pyrophosphate (TPP)
        Synthesized from thiamine (vitamin B1)
        Binds tightly to enzyme, but not covalently
        Functional group is thiazolium ring
        Thiamine deficiency is beriberi
        Neurological disturbances causing [a] Pain [b] Paralysis and atrophy of limbs and/or edema [c] Then death
        Coenzyme TPP mostly used in α-keto acid decarboxylations
        Neither synthesized nor stored
        Alcohol dehydrogenase: Enzyme catalyzes reduction of acetaldehyde to ethanol
        NADH required and regenerates NAD+ for use in glyceraldehyde-3-phosphate dehydrogenase
        With regeneration of NAD+ for glycolysis
        Process is 2 consecutive reactions [1] Pyruvate decarboxylase [2] Alcohol dehydrogenase

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1a Glucose Catabolism: Slides 1-53

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