Enzymes Note M.N. Chatterjea For Nurses

Biological Importance, Medicinal Uses and Inhibitory Mechanism of Enzymes

Biological Importance of Competitive Inhibitors, Non-Competitive Inhibition,Suicide Inhibition,Feedback Regulation and Inhibition,Uses of Enzymes Biological Importance 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"