The pay-off phase Generates 4 ATP, 2 ATP/ .• Generates 4 ATP, 2 ATP/pyruvate ... • Regulates

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  • The pay-off phase

    Converts glyceraldehyde-3-P to pyruvate

    Generates 4 ATP, 2 ATP/pyruvate

    Remember each of these reactions is run in duplicate for 1 molecule of glucose (each glucose produces 2

    glyceraldehyde 3-P)

    Rxn 6: Glyceraldehyde-3-P to 1,3-bisphoshoglycerate

    C. i. Glyceraldehyde-3-phosphate

    dehydrogenase

    ii. Dehydrogenase

    iii. Also called an oxidoreductase

    D. Energy producing step! This

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-1

    B. Mechanism

    D. Energy producing step! This

    step produces NADH

    E. Not a regulatory step

    F. Energy:

    Rxn ATP

    used

    ATP

    made

    NAD

    used

    NADH

    made

    This step

    Overall

  • Rxn 7: 1,3-bisphosphoglcerate to 3-phosphoglycerate

    B. Mechanism is reverse of phosphorylation

    C. i. Phosphoglycerate kinase

    ii. Transferase- kinase! (same as rxn 1 & 3)

    D. Purpose: This is first step where ATP is

    made!

    E. Not a regulatory step

    F. Energy

    Rxn ATP

    used

    ATP

    made

    NAD

    used

    NADH

    made

    This step

    Overall

    Rxn 8: 3-phosphoglycerate to 2-phosphoglycerate

    C. i. Phosphoglycerate mutase

    ii. Isomerase

    iii. Mutase (same as 2 & 5, mutase is enzyme that transfers

    phosphoryl group)

    D. Purpose: Getting ready for the next enzyme

    E. Not a regulatory step

    F. Energy

    Rxn ATP

    used

    ATP

    made

    NAD

    used

    NADH

    made

    This step

    Overall

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-2

  • Rxn 9: 2-phosphoglycerate to phosphoenolpyruvateB. Mechanism

    C. i. Enolase

    ii. Lyase

    iii. non-hydrolytic cleavage

    D. Purpose: To generate a high energy bond

    PEP has a higher phosphoryl group transfer potential than 2-PG

    E. Not a regulatory step

    F. EnergyF. EnergyRxn ATP

    used

    ATP

    made

    NAD

    used

    NADH

    made

    This step

    Overall

    Rxn 10: PEP to pyruvateB. Mechanism is same as previous

    C. i. Pyruvate kinase

    ii. Transferase reaction (kinase)

    D. Purpose: ATP is made!! More energy!!

    E. This is a regulated step!! Not reversible

    G = -31.7 kJ/mol

    F: Energy

    Rxn ATP

    used

    ATP

    made

    NAD

    used

    NADH

    made

    This step

    Overall

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-3

  • Investment v. payoff balance sheet

    Rxn ATP change/glucose NADH change/glucose

    1

    3

    6

    7

    10

    Total

    Thus our payoff is ____________________

    What happens to pyruvate?

    Pyruvate can take 1 of 4 paths next:

    Aerobic conditions

    1. Converts to acetyl CoA (by pyruvate dehydrogenase) for use in the TCA cycle and

    oxidative phosphorylation (leads to more ATP production)

    2. Converts to oxaloacetate , which can then shuttle into the synthesize of glucose 2. Converts to oxaloacetate , which can then shuttle into the synthesize of glucose

    (gluconeogenesis)

    Anaerobic conditions

    3. It is converted to Lactate (animal muscles; lactate used in gluconeogenesis)

    4. It is converted to ethanol (yeast; alcohol fermantation)

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-4

  • What happens to the NADH?

    Need to regenerate NAD+.

    Aerobic conditions:

    Electron transport system (lectures 33 & 34)

    Anaerobic conditions:

    EtOH production consumes

    Lactate production consumes

    Regulation of glycolysis

    Our cells must ALWAYS have energy, so glycolysis is HIGHLY regulated

    As ATP and NADH levels go up and down, glycolysis goes up and down due to specific regulation

    We listed:

    7 steps as unregulated (2, 4-9)

    3 steps (1, 3, 10) as regulated.

    Why are these three steps the regulatory steps?

    Steps 2, 4-9:

    These are the unregulated steps

    Have G close to zero

    Essentially at equilibrium

    Can run in either direction

    (And they are common steps in glucose

    synthesis (gluconeogenesis))

    Steps 1, 3, 10:

    These are the regulated steps

    Have large G

    Therefore not at equilibrium

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-5

  • Regulation at step 1: hexokinase

    Regulates the entry of glucose into glycolysis by controlling the amount of

    glucose-6-P.

    This reaction is controlled by FEEDBACK inhibition

    Hexokinase is inhibited by glucose-6-P (its product!):

    If too much product, inhibits the production of more by turning

    off hexokinase.

    Regulation at Step 3: phosphofructokinase-1 (PFK-1)

    This is the major control point of glycolysis!

    -Once this step happens, we MUST form pyruvate

    -G is too large to overcome (-16.7 kJ/mol)

    -no alternative pathways

    Multiple things regulate PFK-1

    -ATP

    -AMP

    -Citrate

    -Fructose-2,6-bisphosphate-Fructose-2,6-bisphosphate

    A substrate

    (active site has a high affinity for ATP)

    An allosteric inhibitor

    (inhibition site has a lower affinity for ATP)

    Therefore, when ATP concentration low, will only bind at active site. When ATP

    concentration is high, it will bind at both sites.

    If [ATP] is high, PFK-1 is turned off.

    If [ATP} is low, PFK-1 is turned on.

    This should seem logical- if we have energy (high ATP) we do not need to make more

    If we need more energy (low ATP) we need to make more

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-6

  • An allosteric activator

    has a low affinity for AMP

    If [AMP] is high, indicates [ATP] is low, so we need more energy!

    If [AMP] is high, will bind PFK-1 and activate it! Thus we will increase pyruvate

    (and ATP!) production

    Regulation at Step 3: by AMP

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-7

  • Regulation at Step 3: by Citrate

    An allosteric (feedback) inhibitor

    PFK-1 has a low affinity for citrate

    Citrate is synthesized in the TCA cycle from pyruvate

    Therefore, if pyruvate production is high, citrate production will be high.

    So, when [citrate] high, indicates we do not need more pyruvate, so citrate turns off PFK-1 to

    stop glycolysis.

    Regulation at Step 3: by Fructose-2,6-bisphosphate

    Fructose-2,6-BP is an allosteric activator

    PFK-2 has a lower affinity for Fructose-6-P

    than PFK-1.

    Therefore, at high concentrations of

    Fructose-6-P, some will be converted to

    Fructose-2,6-bisphosphate.

    If [Fructose-2,6-bisP] gets too high, it will

    bind to PFK-1, activating it, and increasing

    glycolysis.

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-8

  • Regulation at Step 10: Pyruvate kinase

    High [Fructose 1,6-bisphosphate] activates pyruvate kinase

    High [ATP] inhibits pyruvate kinase

    ATP is both a substrate and an inhibitor of this enzyme!

    Why would we want to regulate this step??

    The intermediates between _____ can be shuttled to other

    pathways, so their production is not a waste.

    Regulation of glycolysis

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-9

  • How do other carbohydrates enter glycolysis?

    1. Starch (glucose polymer)

    In mouth, amylases break starch to glucose monomers

    In stomach, acid breaks starch to glucose monomers

    Glucose is then absorbed through intestinal wall to blood and transported

    Glucose can then enter cells and start glycolysis.

    1/3 of glucose goes to the heart and skeletal muscles

    1/3 of glucose goes to your brain!

    1/3 of glucose to the liver for storage

    2. Disaccharides

    a. Maltose

    b. Sucrose

    c. Lactose

    mannose enters from glycoproteins

    glycerol- results from the breakdown of fat

    Entrance of fructose into glycolysis

    Can enter through liver or muscle

    Liver

    -3 additional reactions

    - Enters glycolysis as 2 molecules of glyceraldehyde-3-P

    Chemistry C483 Fall 2009 Prof Jill Paterson 30-10

  • Muscle

    -Enters the pathway as fructose-6-P

    -This is just 1 additional step!!

    -We use 1 ATP to get to this entry point

    -A muscle specific kinase can phosphorylate fructose

    How much energy do we get from fructose?

    But we miss at least 1 regulatory step!

    We miss step 1 (in both cases), and step 3 (in liver)

    This takes away regulatory steps.

    People who take in large amounts of fructose tend to have additional fat in their livers. People who take in large amounts of fructose tend to have additional fat in their livers.

    -There is an overproduction of pyruvate

    - Pyruvate leads to the production of fats and cholesterol

    How does galactose enter glycolysis?

    Galactose requires 5 reactions to transform it to glucose-6-phosphate

    On your own:

    1. Determine where galactose enters glycolysis

    2. Do an energy count- do we get the same amount of energy for galactose?

    3. Is regulation different from glucose?Chemistry C483 Fall 2009 Prof Jill Paterson 30-11

  • Mannose

    On your own:

    1. Determine where mannose enters glycolysis

    2. Do an energy count- do we get the same amount of energy for mannose?

    3. Is regulation different from glucose?

    Glycerol

    Glycerol is released during the degradation of fatty acids

    2 reactions to become dihydroxyacetone

    -Phosphoryl transfer

    -Oxidation

    -enters glycolysis as dihydroxyacetone

    On your own:On your

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