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Enzyme inhibition and
regulation
Ms Lulembo

1

•

Enzyme inhibitors are molecular agents that interfere with catalysis, slowing
or halting enzymatic reactions
• Inhibitors are the most important pharmacological agents known
Enzyme inhibitors – have provided valuable information about enzyme
mechanisms
- have helped define some metabolic pathways
Two broad classes – Reversible and irreversible
Reversible inhibition
Can be – competitive, uncompetitive, noncompetitive or mixed
A competitive inhibitor (I)
• competes with the substrate for the active site of the enzyme
• while the inhibitor occupies the active site it prevents binding of the
substrate to the enzyme
• competitive inhibitors often resemble the substrate and combine with the
enzyme to form an EI complex, but without leading to catalysis
• thus a competitive inhibitor diminishes the rate of catalysis by reducing the
proportion of enzyme molecules bound to a substrate
2

E

+ S

ES

E+P

+
I

EI
•

•

•

The I is bound reversibly to the enzyme and when more substrate is added
the inhibition is overcome by pulling the enzyme free via breakdown of EI
complex which is in equilibrium with free E and I
...

1
...
Methotraxate
• Is a potent competitive inhibitor of dihydrofolate reductase, an enzyme
which plays a role in the biosynthesis of purines and pyrimidines
• It is a structural analogue of dihydrofolate, a substrate for dihydrofolate
reductase
• It binds to the enzyme 1000-fold more tightly than the natural substrate and
inhibits nucleotide base synthesis
• Its used to treat cancer
Uncompetitive inhibition
• The inhibitor binds only to the enzyme-substrate complex
E + S

ES + I

E+P

Ki
ESI
•
•
•

Because some unproductive ESI are always present, the Vmax is lower in the
presence of the inhibitor than in its absence
The uncompetitive inhibitor lowers the apparent Km
...
To maintain
equilibrium between E and ES more S binds to E
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•

It can not be overcome by addition of more substrate

Non-competitive inhibition which is also reversible,
• The inhibitor and substrate can bind simultaneously to an enzyme molecule and
binding sites do not overlap
• A noncompetitive inhibitor acts by decreasing the turnover number rather than by
diminishing the proportion of enzyme molecules that are
bound to substrate
• Can not be overcome by increasing substrate concentration

E + I
Ki

EI
•
•

S

S

ES + I

E+P

Ki
ESI

X

The Vmax is decreased to a new apparent Vmax whereas the Km remains unchanged
The inhibitor simply lowers the concentration of functional enzyme; behaves like a
more dilute solution of enzyme
• If Ki for I binding to empty enzyme E is not the same as that for I binding to occupied
ES, mixed inhibition may be observed
In mixed inhibition
• a single inhibitor hinders both the binding of substrate and decreases the turnover
number of enzyme
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Irreversible inhibitor
• An irreversible inhibitor dissociates very slowly from its target enzyme because it
becomes very tightly bound to the enzyme, either covalently or noncovalently
eg -action of nerve gas on acetylcholinesterase, an enzyme that plays an
important role in the transmission of nerve impulses
-heavy metal ions (Ag+, Hg 2+)
-iodoacetamide
•

Some irreversible inhibitors are important drugs e
...

– Penicillin acts by covalently modifying the enzyme transpeptidase, pr

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