Enzyme Inhibition/Enzyme Inhibitors

ENZYME INHIBITION/ENZYME INHIBITORS
Enzyme inhibitor is defined as a substance which binds with the enzyme and brings
about a decrease in catalytic activity of that enzyme. Enzyme inhibition is classified
under three major groups:
• Competitive inhibition (Reversible).
• Non-competitive inhibition (Irreversible or reversible).
• Allosteric inhibition.
Competitive Inhibition
When the active site or catalytic site of an enzyme is occupied by a
substance other than the substrate of that enzyme, its activity is inhibited.
The type of inhibition of this kind is known as competitive inhibition. This is a type of
reversible inhibition. In such inhibition both the ES and EI (Enzyme-Inhibitor)
complexes are formed during the reaction.
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However, the actual amounts of ES and EI will depend on:
• Affinity between enzyme and substrate/inhibitor,
• Actual concentrations (amounts) of substrate and inhibitor present, and
• Time of preincubation of enzyme with the substrate or inhibitor.
So the affinity of the substrate for the enzyme is progressively decreased with the
increase in conc. Of inhibitor lowering the rate of enzymatic reaction. Thus, the Km is
high, but Vmax is the same in competitive inhibition.
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However, when the concentrated substrate is increased, the effect of inhibitor can be
reversed forcing it out from EI complex.
Following are few examples of competitive inhibitors.
Competitive Inhibitors:
Allopurinol: A drug used for treatment of Gout. Uric acid is formed in the body by
oxidation of hypoxanthine by the enzyme Xanthine oxidase. Allopurinol
structurally resembles hypoxanthine and thus by competitive inhibition, the drug
inhibits the enzyme xanthine oxidase thus reducing uric acid formation.
Sulphonamides: A very commonly used antibacterial agent. Para-aminobenzoic acid
(PABA) is essential for synthesis of folic acid by the enzyme action. Folic acid is needed
for bacterial growth and survival. Bacterial wall is impermeable to folic acid.
Sulphonamide drugs are structurally similar to PABA and competitively inhibit enzyme
action. Thus, folic acid is not synthesised and
4 growth of bacteria suffers and they die.
Methotrexate: A drug used for cancer therapy. Chemically it is 4-amino-N10-methyl
folic acid. The drug structurally resembles folic acid. Hence it competitively inhibits
“folate reductase” enzyme and prevents formation of FH4. Hence, DNA synthesis
suffers.
MAO inhibitors: The enzyme Monoamine oxidase (MAO) oxidises pressor amines
catecholamines, e.g. epinephrine and norepinephrine. Drugs Ephedrine and
Amphetamine structurally resemble catecholamines. Thus, when administered they
can competitively inhibit the enzyme “MAO” and prolong the action of pressor amines.
Physostigmine: “Acetylcholinesterase” is the enzyme which hydrolyses acetylcholine to
form choline and acetate. Physostigmine is a drug which competitively inhibits
acetylcholinesterase and prevents destruction of acetylcholine. Thus, continued
presence of acetylcholine in post-synaptic region prolongs the neural impulse.
Dicoumarol: Used as an anticoagulant. It is structurally similar to vitamin K and can act
as an anticoagulant by competitively inhibiting vitamin K.
Succinylcholine: It is used as a muscle relaxant. Succinylcholine is structurally similar
to acetylcholine. It competitively fixes on post-synaptic receptors. As it is not hydrolysed
easily by the enzyme acetylcholinesterase, produces continued depolarisation with
consequent muscle relaxation.
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Non-competitive Inhibition
This is of two different types namely (i) reversible and (ii) irreversible. This occurs
when the substances not resembling the geometry of the substrate do not exhibit mutual
competition. Most probably the sites of attachment of the substrate and
inhibitor are different. The inhibitor binds reversibly with a site on enzyme other
than the active site. So the inhibitor may combine with both free enzyme and ES
complex. This probably brings about the changes in 3D structure of the enzyme
inactivating it catalytically.
In noncompetitive inhibition Vmax is lowered, but Km is kept constant.
Non-competitive Irreversible Inhibitors

Iodoacetate: An irreversible inhibitor of enzymes like glyceraldehyde-3-p
dehydrogenase and papain. It combines with–SH group at the active site of the
enzyme inactivating the enzyme.
Heavy metal ions like Ag, Hg also act as irreversible noncompetitive inhibitor.
Fluoride: Inhibits the enzyme enolase by removing Mg++ and Mn++ and stops
glycolysis.
BAL (British anti Lewesite): Called Dimercaprol, used as antidote for heavy metal
poisoning. The heavy metals act as enzyme poisons by reacting with –SH groups. BAL
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has several –SH groups with which the heavy metal ions react, thus removing their
poisonous effects.
Disulfiram (Antabuse): Used in treatment of alcoholism, the drug irreversibly inhibits
the enzyme aldehyde dehydrogenase preventing further oxidation of acetaldehyde
which accumulates and produces sickening effect leading to aversion to alcohol.
Di-isopropyl fluorophosphate (DFP): Inhibits enzymes with serine in their active site
e.g. acetylcholine esterase.
Suicide Inhibition
It is a special type of irreversible noncompetitive inhibition. In this type of
inhibition, substrate analogue is converted to a more effective inhibitor with
the help of the enzyme to be inhibited. The so formed new inhibitor binds irreversibly
with the enzyme.
• Allopurinol
The best example of suicide inhibition. The drug is used in treatment of gout, as it
inhibits the enzyme xanthine oxidase thus decreasing the uric acid formation. But
allopurinol gets oxidised by the enzyme xanthine oxidase itself to form
“alloxanthine” a more potent effective and stronger inhibitor of xanthine
oxidase thus potentiating the action of allopurinol.
• Aspirin
Most commonly used drug for relieving pain. Antiinflammatory action of aspirin is also
based on the suicide inhibition. Aspirin acetylates a serine residue in the active centre of
cyclooxygenase thus inhibiting the PG synthesis and the inflammation.
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• 5-fluorouracil
Used in cancer therapy, 5-fluorouracil (5-FU) is converted to fluorodeoxyuridylate
(Fdump) by the enzymes of the salvage pathway. Fdump so formed inhibits the
enzyme thymidylate synthase thus inhibiting nucleotide synthesis.
Allosteric Inhibition and Allosteric Enzymes

There is a mixed kind of inhibition when the inhibitor binds to the enzyme at a site other
than the active site but on a different region in the enzyme molecule called allosteric
site. Allosteric inhibition does not follow the Michaelis-Menten hyperbolic
kinetics. Instead it gives a sigmoid kinetics.
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Allosteric inhibitors shift the substrate saturation curve to the right. However as
opposite to inhibitors, the presence of activators shifts the curve to the left.
Types:
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Allosteric enzymes are of K and M series according to their kinetics.
• In K-enzymes, e.g. aspartate carbamoylase and phosphofructokinase, the allosteric

inhibitor lowers the substrate affinity to raise the Km of the enzyme; but the Vmax is
unchanged.
• In M-enzymes, e.g. acetyl-CoA carboxylase, the allosteric inhibitor reduces the

maximum velocity but no change in Km or substrate affinity. Allosteric activators
produce a fall in K enzymes and a rise in Vmax in M enzymes.
• When the final product allosterically inhibits the enzyme, it is called as feedback
allosteric inhibition.
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ENZYME INHIBITION/ENZYME INHIBITORS

• Competitive inhibition (Reversible).

• Non-competitive inhibition (Irreversible or reversible).

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In noncompetitive inhibition Vmax is lowered, but Km is kept constant.

Non-competitive Irreversible Inhibitors

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Allosteric Inhibition and Allosteric Enzymes

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• In K-enzymes, e.g. aspartate carbamoylase and phosphofructokinase, the allosteric

• In M-enzymes, e.g. acetyl-CoA carboxylase, the allosteric inhibitor reduces the

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