5. Feedback inhibition and Precursor activation

6. Feedback Inhibition
If the product of a series of enzymatic reactions, e.g., an amino acid, begins to accumulate within the cell, it may specifically inhibit the action of the first enzyme involved in its synthesis (red bar). Thus further production of the enzyme is halted.

8. Precursor Activation
The accumulation of a substance within a cell may specifically activate (blue arrow) an enzyme that sets in motion a sequence of reactions for which that substance is the initial substrate. This reduces the concentration of the initial substrate.

9. In the case if feedback inhibition and precursor activation, the activity of the enzyme is being regulated by a molecule which is not its substrate.
In these cases, the regulator molecule binds to the enzyme at a different site than the one to which the substrate binds.
When the regulator binds to its site, it alters the shape of the enzyme so that its activity is changed. This is called an allosteric effect.

10. In feedback inhibition, the allosteric effect lowers the affinity of the enzyme for its substrate.
In precursor activation, the regulator molecule increases the affinity of the enzyme in the series for its substrate.

11. The rate expression for allosteric enzymes is:
Where n=co- operativity coefficient
n>1 indicates positive co-operativity(activator)
n<1 …inhibitor
The co-operativity coefficient can be determined by rearranging the above eqn:

14. These inhibitors are usually substrate analogs – compete with substrate to occupy the active site of the enzyme
results in the formation of dead-end complex
At high substrate concentrations the effect of the inhibitor will be reduced and the max. reaction rate will be obtained

16. Competitive Inhibition
For example, malonic acid resembles succinic acid because both have two carboxyl groups.
Malonic acid inhibits the action of succinic dehydrogenase on succinic acid by clogging the active site on the enzyme
Competitive Inhibition

17. Competitive Inhibition

18. the affinity of enzyme for substrate
COMPETITIVE INHIBITION………………….
Vm remains unchanged and KM is increased by a factor of , thus decreases
the affinity of enzyme for substrate

19. Vm remains unchanged and KM is increased by a factor of*

20. A special case of COMPETITIVE INHIBITION
Normally the competitive inhibitor bears some structural similarity to the substrate and often is a reaction product  Product inhibition
In this case I = P
Therefore,
e.g. Inhibition of lactase by galactose

21. Competitive inhibitiors -used as therapeutic agents in medicine or as insecticides & herbicides.
Ethanol is Used Therapeutically as a Competitive Inhibitor to Treat Ethylene Glycol Poisoning.
Ethylene glycol, a constituent of antifreeze - itself is not lethally toxic - the harm is done by oxalic acid, the oxidation product of ethylene glycol.

22. Competitive Inhibition
The kidneys - severely damaged by the deposition of oxalate crystals.
The first committed step in this conversion is the oxidation of ethylene glycol to an aldehyde by alcohol dehydrogenase.
This reaction can be effectively inhibited by administering a nearly intoxication dose of ethanol. The basis of this effect is the ethanol is a competing substrate and so it blocks the oxidation of ethylene glycol to aldehyde products.
The ethylene glycol is then excreted harmlessly.
Competitive Inhibition

23. Competitive Inhibition

24. Uncompetitive inhibitors bind to the ES complex only and have no affinity for the free enzyme itself…..
i.e. the inhibitor can bind to the modified form of enzyme.
This occurs when the inhibitor binds to a site which only becomes available after the substrate(s) has bound to the active site of the enzyme.

26. Un competitive InhibitionX

27. Vm and KM both are affected by a by a factor of

28. Vm and KM both are affected*
1/s *

29. A special case of UNCOMPETITIVE INHIBITION-----Substrate Inhibition
This occurs at high substrate concentrations in about 20% of all know enzymes (e.g. invertase is inhibited by sucrose)
It is primarily caused by more than one substrate molecule binding to an active site meant for just one.
If the resultant complex is inactive, this type causes a reduction in the rate of reaction at high substrate concentrations.

30. ‘v’ is inversely proportional to the substrate concentration ‘s’
Substrate Inhibition
Substrate Inhibition
‘v’ is inversely proportional to the substrate concentration ‘s’

31. Optimum substrate concentration…

34. Noncompetitive inhibitors bind to the enzyme on sites other than the active site and reduce the enzyme affinity for the substrate.
This inhibitor can combine with either the free enzyme or with the enzyme substrate complex to produce a dead-end complex

35. Noncompetitive Inhibition

36. KM remains unchanged and Vm is changed

37. KM remains unchanged and Vm is changed*
1/s

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