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Enzyme inhibitors are molecules that interact in some way with the enzyme to
prevent it from working in the normal manner; thus they decrease the rate of
an enzyme-catalyzed reaction.
The nerve gas diisopropyl phosphorofluoridate forms a strong covalent bond with
the hydroxyl group of the serine residue at the active site of acetylcholinesterase.
Irreversible Inhibition
When a nerve makes a muscle cell contract, it gives the cell a tiny squirt of acetylcholine
molecules. Acetylcholine is called a neurotransmitter because it acts as a messenger
between the nerve and the final destination (in this case, the muscle cell).
Once they have performed the proper function, the acetylcholine molecules must be
destroyed; otherwise, the resulting excess of this substance will hyperstimulate glands and
muscle, producing convulsions, choking, and other distressing symptoms. Many victims of
exposure to this nerve gas suffer paralysis or even death.
Irreversible Inhibition
The irreversible inhibition of this enzyme takes place via the formation
of a covalent bond between the phosphorus atom and the hydroxyl
oxygen of the serine residue in the enzyme.
The inhibitor competes for the same active site as the substrate
molecule. The inhibitor may interact with the enzyme at the active site,
but no reaction takes place.
where
Competitive Inhibition
Note that the complex EI does not react with S to form products. Applying the
steady-state approximation for ES, we obtain:
[]
= [I]
(10)
1+ +[]
I
Which has the same form as the MichaelisMenten expression (Eq. 6), except that
the KM term has been modified by 1 + [I] I , thereby reducing .
Competitive Inhibition
The LineweaverBurk equation is given by
1 [I] 1 1
= 1+ + (11)
I []
Thus, a straight line results when 1/r is plotted versus 1/[S] at constant [I]. The
difference between this Equation and the rearranged Michaelis-Menten expression
(Eq. 9) is that in the former, the slope is enhanced by the factor 1 + [I] I .
Competitive Inhibition
The intercept on the 1/r axis is the same for because rmax does not
change.
Competitive Inhibition
Dividing the MichaelisMenten expression (Eq. 6) by Equation (10), we
obtain
Because malonic acid resembles succinic acid in structure, it can combine with the
enzyme, although no product is formed in this reaction.
Uncompetitive Inhibition
An uncompetitive inhibitor does not bind to the free enzyme; instead,
it binds reversibly to the enzymesubstrate complex to yield an inactive
ESI complex.
where
Uncompetitive Inhibition
The ESI complex does not form a product. Again, because I does not
interfere with the formation of ES, uncompetitive inhibition cannot be
reversed by increasing the substrate concentration.
Uncompetitive Inhibition
The initial rate is given by
(12)
(13)
Thus, a straight line is obtained by plotting 1/r versus 1/[S] at constant [I]. The
difference between this Equation and the rearranged Michaelis-Menten expression
(Eq. 9) is that the intercept on the 1/r axis is altered by the factor 1 + [I] I , but
the slope remains the same.
Uncompetitive Inhibition
Uncompetitive Inhibition
Dividing the MichaelisMenten expression (Eq. 6) by Equation (12), we get
Noncompetitive inhibition.
The inhibitor binds to a
site other than the active
site.
The ESI complex does not
lead to product formation.
Noncompetitive (Mixed) Inhibition
The binding of the inhibitor has no effect on the substrate binding, and vice versa.
The reactions are
Neither EI nor ESI forms products. Because I does not interfere with the formation
of ES, noncompetitive inhibition cannot be reversed by increasing the substrate
concentration.
Noncompetitive (Mixed) Inhibition
The initial rate is given by
(14)
Comparing Equation (14) with the MichaelisMenten expression (Eq. 6), we see
that rmax has been reduced by the factor 1 + [I] I but KM is unchanged.
Noncompetitive (Mixed) Inhibition
The LineweaverBurk equation is given by
(15)
We see that a plot of 1/r versus 1/[S] gives a straight line with an
increase in slope and intercept on the 1/r axis.
Noncompetitive Inhibition
Noncompetitive Inhibition
Dividing the MichaelisMenten expression (Eq. 6) by Equation (14), we get