Enzyme inhibition in brief and their examples

Enzyme inhibition

1. Presented by:
Jasmine Juliet
Biochemistry,
Agricultural College&
Research Institute, Madurai.

2. Enzyme -Introduction
Enzymes are biocatalystspresent in cells that speed up
biochemical reactions without getting itself destroyed in the
reaction.
Enzymes catalysea reaction by reducing the activation energy
needed for the reaction to occur.
However, enzymes need to be tightly regulated to ensure that levels
of the product do not rise to undesired levels.
This is accomplished byenzyme inhibition.

4. Enzyme -Inhibition
Enzyme inhibitors are molecules that bind to enzymes and
decrease their activity.
Inhibitor binding is either reversible or irreversible.
I.Irreversible inhibitorsusually react with the enzyme and change
it chemically.
The enzyme becomes permanently inactive.
These inhibitors modify key amino acid residues needed for
enzymatic activity.

5. Enzyme -Inhibition
II. Reversible inhibitors bind non-covalently with the enzyme.
The inhibition can be reversedon removal of the inhibitor from the
enzyme.
Most biological inhibitions are reversible and are involved in the
regulation of metabolism.
Not all molecules that bind to enzymes are inhibitors; enzyme
activatorsbind to enzymes and increase their enzymatic activity.

6. Enzyme -Introduction
There are three different reversible inhibitions:
Competitive inhibition
Non competitive inhibition
Uncompetitive inhibition

9. Enzyme –Competitive Inhibition
In competitive inhibition, the inhibitor (I) competes for the
active site and binds to the active site.
Thus, it prevents the substrate from binding to the active site.
Binding of the inhibitor inhibits the reaction and does not produce
any product.
E + I →EI (EI →No product formation)
Structural analogsof the substrate act as competitive inhibitors.

10. Enzyme –Competitive Inhibition
Eg: (i) Malonateis the competitive inhibitor for the enzyme
Succinatedehydrogenaseand
(ii) Allopurinolis the competitive inhibitor for the enzyme
Xanthineoxidase.
In competitive inhibition, V
maxfor the enzyme is not affected
since once there is formation of ES complex the reaction proceeds
normally but, K
m increases.
Increasing substrate concentration overcomes competitive
inhibition.

12. Enzyme –Non-competitive Inhibition
Inhibitor binds to the enzyme at a site other than the active site and
cause inhibition.
The inhibitor may bind to a free enzyme forming EI complex or to
the ES complexto form ESI complex.
E + I → EI(or)ES + I → ESI
Binding of the inhibitor to the enzyme changes the structure and
shape of the enzyme.
This affects the rate of reaction of the enzyme.
V
maxfor the enzyme is lowered; but K
m remains unaltered.

14. Enzyme -UncompetitiveInhibition
The inhibitor binds to the enzyme at a site other than the
active site.
The inhibitor can bind only to the ES complex.
ES + I → ESI
Uncompetitive inhibition works best when substrate
concentration is high.
Both V
maxand K
mfor the enzyme are lowered.

17. Enzyme -Introduction

20. AllostericEnzymes
Some enzymes are reversibly inhibited or activated by the
presence of metabolites that are not their substrate or product.
The enzymes controlled in this way usually have additional
binding site other than the active site.
The binding of inhibitor or activators at distant site (allosteric
site) from active site often bring about conformational
changes in the enzyme molecule which may decrease or
increase its catalytic activity.

21. Thus, allostericenzymes are usually composed of multiple binding
sitesand often shows sigmoidalgraph of initial rate versus [S] and
therefore do not obey MichaelisMentenkinetics.
The kinetic properties of allostericenzymes are often explained in terms
of a conformational change between a low-activity, low-affinity “tense”
or T stateand a high-activity, high-affinity “relaxed” or R state.
These structurally distinct enzyme forms have been shown to exist in
several known allostericenzymes.

22. Aspartatetranscarbamoylase(ATCase) is a typical example of allosteric
enzyme.
This enzyme catalyzes the first step in the biosynthesis of pyrimidines, the
condensation of aspartateand carbamoylphosphate to form N-carbamoyl
aspartate.
This pathway will ultimately yield pyrimidinenucleotide such as cytidine
triphosphate(CTP).
ATCaseis activated by ATP and inhibited by CTP.
ATCasecontains a regulatory subunit to which the effectormolecules bind
and a catalytic subunit which contains the active site for substrate binding.

23. Binding of CTP to the regulatory subunit causes the enzyme to
change its conformation and shift to the inactive T state, thereby
inhibiting the biosynthesis of pyrimidines.
Whereas, binding of ATP favoursactive R state enhancing the
biosynthesis of pyrimidines.
Since CTP, an end product of pyrimidinebiosynthetic pathway is
inhibiting the pathway, this kind of regulation is also called as
feedback inhibition.