Competitive inhibition
Encyclopedia
Competitive inhibition is a form of enzyme inhibition
where binding of the inhibitor to the active site on the enzyme
prevents binding of the substrate
and vice versa.
In virtually every case, competitive inhibitors bind in the same binding site
as the substrate, but same-site binding is not a requirement. A competitive inhibitor could bind to an allosteric site of the free enzyme and prevent substrate binding, as long as does not bind to the allosteric site when the substrate is bound.
In competitive inhibition, the maximum velocity (
) of the reaction is unchanged, while the apparent affinity of the substrate to the binding site is decreased (the 
dissociation constant is apparently increased). The change in 
(Michaelis-Menten constant) is parallel to the alteration in 
. Any given competitive inhibitor concentration can be overcome by increasing the substrate concentration in which case the substrate will outcompete the inhibitor in binding to the enzyme.
, such that initial rate of reaction, 
, is given by
where
, 
is the inhibitor's dissociation constant and 
is the inhibitor concentration.
remains the same because the presence of the inhibitor can be overcome by higher substrate concentrations. 
, the substrate concentration that is needed to reach 
, increases with the presence of a competitive inhibitor. This is because the concentration of substrate needed to reach 
with an inhibitor is greater than the concentration of substrate needed to reach 
without an inhibitor.
is modified to include binding of the inhibitor to the free enzyme:
Note that the inhibitor does not bind to the ES complex and the substrate does not bind to the EI complex. It is generally assumed that this behavior is indicative of both compounds binding at the same site, but that is not strictly necessary. As with the derivation of the Michaelis-Menten equation, assume that the system is at steady-state, i.e. the concentration of each of the enzyme species is not changing.
Furthermore, the known total enzyme concentration is
, and the velocity is measured under conditions in which the substrate and inhibitor concentrations do not change substantially and an insignificant amount of product has accumulated.
We can therefore set up a system of equations:
where
, 
and 
are known. The initial velocity is defined as 
, so we need to define the unknown 
in terms of the knowns 
, 
and 
.
From equation , we can define E in terms of ES by rearranging to
Dividing by
gives
As in the derivation of the Michaelis-Menten equation, the term
can be replaced by the macroscopic rate constant 
:
Substituting equation into equation , we have
Rearranging, we find that
At this point, we can define the dissociation constant for the inhibitor as
, giving
At this point, substitute equation and equation into equation :
Rearranging to solve for ES, we find
Returning to our expression for
, we now have:
Since the velocity is maximal when all the enzyme is bound as the enzyme-substrate complex,
.
Replacing and combining terms finally yields the conventional form:
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
where binding of the inhibitor to the active site on the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
prevents binding of the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
and vice versa.
Mechanism
In competitive inhibition, at any given moment, the enzyme may be bound to the inhibitor, the substrate, or neither, but it cannot bind both at the same time.In virtually every case, competitive inhibitors bind in the same binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
as the substrate, but same-site binding is not a requirement. A competitive inhibitor could bind to an allosteric site of the free enzyme and prevent substrate binding, as long as does not bind to the allosteric site when the substrate is bound.
In competitive inhibition, the maximum velocity (
) of the reaction is unchanged, while the apparent affinity of the substrate to the binding site is decreased (the dissociation constant is apparently increased). The change in (Michaelis-Menten constant) is parallel to the alteration in . Any given competitive inhibitor concentration can be overcome by increasing the substrate concentration in which case the substrate will outcompete the inhibitor in binding to the enzyme.Equation
Competitive inhibition increases the apparent value of the Michaelis-Menten constant,, such that initial rate of reaction, , is given by
where
, is the inhibitor's dissociation constant and is the inhibitor concentration. remains the same because the presence of the inhibitor can be overcome by higher substrate concentrations. , the substrate concentration that is needed to reach , increases with the presence of a competitive inhibitor. This is because the concentration of substrate needed to reach with an inhibitor is greater than the concentration of substrate needed to reach without an inhibitor.Derivation
In the simplest case of a single-substrate enzyme obeying Michaelis-Menten kinetics, the typical schemeis modified to include binding of the inhibitor to the free enzyme:
Note that the inhibitor does not bind to the ES complex and the substrate does not bind to the EI complex. It is generally assumed that this behavior is indicative of both compounds binding at the same site, but that is not strictly necessary. As with the derivation of the Michaelis-Menten equation, assume that the system is at steady-state, i.e. the concentration of each of the enzyme species is not changing.
Furthermore, the known total enzyme concentration is
, and the velocity is measured under conditions in which the substrate and inhibitor concentrations do not change substantially and an insignificant amount of product has accumulated.We can therefore set up a system of equations:
where
, and are known. The initial velocity is defined as , so we need to define the unknown in terms of the knowns , and .From equation , we can define E in terms of ES by rearranging to
Dividing by
gives
As in the derivation of the Michaelis-Menten equation, the term
can be replaced by the macroscopic rate constant :Substituting equation into equation , we have
Rearranging, we find that
At this point, we can define the dissociation constant for the inhibitor as
, givingAt this point, substitute equation and equation into equation :
Rearranging to solve for ES, we find
Returning to our expression for
, we now have:Since the velocity is maximal when all the enzyme is bound as the enzyme-substrate complex,
.Replacing and combining terms finally yields the conventional form:
See also
- Schild regressionSchild regressionSchild regression analysis, named for Heinz Otto Schild, is a useful tool for studying the effects of agonists and antagonists on the cellular response caused by the receptor or on ligand-receptor binding....
for ligand receptor inhibition