Biological Importance, Medicinal Uses and Inhibitory Mechanism of Enzymes

Biological
Importance Competitive Inhibition

1:
Allopurinol Structurally Resembles Hypoxanthine Use For High Uric Acid
Treatment

    Detail:
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.

2: Sulphonamides
Drugs Are Structurally Similar To PABA Hinder Folic Acid Synthesis In Bacteria

    Details: 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
growth of bacteria suffers and they die.

3: Methotrexate
Structurally Resemble Folic Acid And Use In Chemotherapy For The Treatment Of
Cancer Cell By Hindering Synthesis Of DNA And RNA

    Detail:
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.

4: MAO
Inhibitors Chemically Resembles Catecholamines

    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.

5: Physostigmine
Competitive Inhibitor Of Acetylcholinesterase

    “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.

6: Dicoumarol
Similar To Vitamin K And Can Act As An Anticoagulant

    Used
as an anticoagulant. It is structurally similar to vitamin K and can act as an
anticoagulant by competitively inhibiting vitamin K.

7: Succinylcholine
is structurally similar to acetylcholine

    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.

2.
Non-Competitive Inhibition

This
is of two different types namely

(i)Reversible

(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.

Effect
on Kinetics Reaction

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

    If
the inhibitor can be removed from its site of binding without affecting the
activity of the enzyme, it is called as Reversible-Non-competitive
Inhibition.

    If
the inhibitor can be removed only at the loss of enzymatic activity, it is
known as Irreversible Non-competitive Inhibition.

v         However, the kinetic properties in case of both are the same.

Biological
Importance Of Non-Competitive Irreversible Inhibitors

    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.

    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.

 

Competitive Inhibition	Non- Competitive Inhibition
Reversible	Reversible or Irreversible
Inhibitor and substrate resemble each other in structure	Does not resemble
Inhibitor binds the active site	Inhibitor does not bind the active site
C max is same	Vmax lowered
Km increased	Km unaltered
Inhibitor cannot bind with ES complex	Inhibitor can bind with ES complex
Lowers the substrate affinity to enzyme	Does not change substrate affinity for the enzyme
Complex is E-	Complex is E-S-I or E-I

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.

Examples

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. Anti Inflammatory
action of aspirin is also based on the suicide inhibition. 

    Aspirin acetylates a
serine residue in the active center of cyclooxygenase thus inhibiting the PG
synthesis and the inflammation.

Feedback
Regulation and Inhibition

    Feedback regulation of an enzyme occurs when a
product of the reaction binds to an allosteric site on the enzyme and affects
its catalytic activity. 

    While feedback inhibition, the cell responds to the
amount of reaction product in order to regulate its further production.

Control
Of Enzyme Degradation: Ubiquitin-Protease Pathway

    In
animals, many proteins are degraded by the ubiquitin protease pathway.(
Proteosome 26s Protein)

Clinical
Significance or Importance of Biodegradation

    Evidences
now suggest that dysfunctions of the ubiquitin proteasome pathway contribute to
the accumulation of aberrantly folded protein species characteristic of several
neurodegenerative diseases.

Uses
of Enzymes

Enzymes
are used as follows:

(a)
Enzymes estimation in serum and body fluids for diagnosis and prognosis

(b)
Enzyme used as laboratory reagent

(c)
Therapeutic uses of enzymes

(a)
Enzyme estimation in serum and body fluids: Various enzyme estimations in serum
and body fluids viz. CS fluid, peritoneal/pleural fluids have been used for
diagnosis and prognosis of diseases. 

    Serial estimations of Alanine transaminase
(AL-T) in serum have been use for prognosis of viral hepatitis (for
details—refer to chapter on “Enzymes and Isoenzymes of Clinical Importance”).

(b)
Enzyme used as laboratory reagent: Some enzymes are used for estimation of
biomolecules in serum. Examples

    “Glucose
oxidase” enzyme is used for estimation of “true glucose” in blood and body
fluids. 

Enzyme “uricase” is used for estimation of serum uric acid.

Enzyme
“urease” is used for estimation of urea in blood and body fluids.

(c)
Therapeutic uses of enzymes: Enzymes have been used for treatment purposes.

Reference:

Notes Made By The Help of “The Text Book of Medical Biochemistry By MN. Chatterjea 8th Edition“