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Regulation of Glycolysis

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In most tissues it is part of ATP production system ... 2.810 J/mole = -2.81 kJ/mole. Similarly ?G can be calculated across all of the reactions ... – PowerPoint PPT presentation

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Title: Regulation of Glycolysis


1
Regulation of Glycolysis
2
Approach
  • (1) What is the function of glycolysis
  • -Regulation must relate to function
  • (2) What are the regulatory steps and how are
    they regulated?

3
Function of glycolysis
  • In most tissues it is part of ATP production
    system
  • it must be sensitive to the energy
    status of the cell
  • (ii) In liver and adipose tissue- it is often
    part of the process that converts excess carbs to
    fat
  • In these tissues there will be different
    controls

4
What are the potential regulatory steps?
5
Calculate the free energy changes across the 10
reactions of glycolysis
  • e.g. Phosphohexoisomerase
  • Keq for G6P-F6P 0.5
  • Concentrations
  • G6P 8.3 x 10-5 M
  • F6P 1.4 x 10-5 M
  • ?Go -2.303 RT log Keq
  • -(2.303 x 8.31 x 310 x (-0.3))
  • 1776 J/mole
  • ?G ?Go 2.303 RT log product/reactant
  • -2.810 J/mole
  • -2.81 kJ/mole

6
  • Similarly ?G can be calculated across all of the
    reactions

7
  • Free energy profile -
  • almost all of the free-energy released during
    glycolysis occur in just 3 steps HK, PFK, PK
  • These three reactions are displaced far from the
    thermodynamic equilibrium
  • The other reactions of glycolysis are close to
    equilibrium

8
So what?
9
  • Net Flux 1nmole/sec
  • Which steps are likely to be rate limiting?
  • The Far-from-equilibrium reactions are holding up
    the close-to-equilibrium reactions
  • The far-from-equilibrium reactions are the rate
    limiting reactions

10
  • If the close-to-equilibrium reaction is activated
    it can not make a difference to the overall rate
    of the pathway
  • However, if we can activate the
    far-from-equilibrium (irreversible) reactions ,
    we can make the pathway go faster.

11
Glycolysis
  • We have identified the irreversible steps HK,
    PFK, PK
  • Control of these key enzymes can make the
    glycolysis proceed faster How?

12
Regulation of glycolysis by Adenine Nucleotides
  • In tissues where the primary function of
    glycolysis is ATP production (muscle, Brain etc),
    it need to be sensitive to ATP, directly or
    indirectly.
  • ATP is too important to be allowed to undergo
    large changes in concentration.
  • AMP can reflect ATP, inversely as follows

13
  • This reaction is close to equlibrium in vivo Keq
    0.44
  • A small change in ATP translates into large
    increase in AMP

14
How?
  • Eg.
  • Total Adenine nucleotide 5 mM
  • ATP 4.8 ADP 0.185 AMP 0.015
  • Due to the action of Adenylate kinase a 4
    reduction in ATP will lead to a 300 increase
    in AMP.
  • ATP 4.6 ADP 0.34 AMP 0.06

15
  • Thus AMP serves as a very sensitive indicator
    of small changes in ATP .
  • Are the rate limiting glycolytic steps sensitive
    to AMP?
  • i) Phosphofructokinase is allosterically
    inhibited by ATP and activated by AMP
  • ii) Hexokinase is allosterically inhibited by
    glucose-6-P

16
(No Transcript)
17
Slow flux through Glycolysis
18
Rapid Flux through Glycolysis
Increased demand for ATP Low ATP and High AMP
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