Enzyme inhibition (competitive, non-competitive and uncompetitive)

INTRODUCTION:

• Chemical substances (organic/inorganic) interfering with enzyme activity are “Inhibitors/negative modifiers”.
• Process is called “Enzyme inhibition”.

TYPES:

Classified as:

• Competitive inhibition
• Non-competitive inhibition
• Un-competitive inhibition

COMPETITIVE INHIBITOR:

• When active/catalytic site of an enzyme is occupied by substance other than substrate of that enzyme, its activity is inhibited. 
• Inhibitor must be structural analog of substrate. 
• In such inhibition, both ES & EI (Enzyme-Inhibitor) complexes are formed.
• With the increase in conc. of inhibitor lowers the rate of enzymatic reaction. 
• Thus, Km is high, but Vmax is same.
•  Also, when concentration of substrate is increased, inhibitor effect reversed forcing it out from EI complex.

In presence of competitive inhibitor, the MM equation becomes:

 Clinical importance of competitive inhibition:

NON-COMPETITIVE INHIBITION:

• Inhibitor usually binds to different domain on enzyme, e.other than substrate binding sit
• The inhibitor binds reversibly with enzyme site other than active site. 
• So inhibitor may combine with both free enzyme and ES complex.
• Velocity (Vmax) is reduced. 
• But Km value is not changed, because remaining enzyme molecules have same affinity for substrate.
• Strong affinity for inhibitors prevents catalysis possibly due to distortion in enzyme conformation.
• Ex: Poisons (iodoacetate, heavy metal ions – lead, mercury) & oxidizing agents act as irreversible non-competitive inhibitors.

• If inhibitor can be removed from its site of binding without affecting enzyme activity – Reversible-Non-competitive Inhibition.
• If inhibitor can be removed only at loss of enzymatic activity by forming a covalent bond – Irreversible Non-competitive Inhibition. Eg:Carbonic anhydrase

Clinical importance of non-competitive inhibition:

• Cyanide inhibits cytochrome oxidase.
• Fluoride will remove magnesium and manganese ions inhibiting enzyme, enolase in glycolysis.
• Iodoacetate would inhibit enzymes (Glyceraldehyde-3-P dehydrogenase, papain)  having –SH group in their active centers.
• Non-competitive inhibitor of carbonic anhydrase is Acetazolamide
• BAL (British Anti-Lewisite; Dimercaprol) is used as an antidote for heavy metal poisoning.
• Disopropyl fluorophosphates (DFP) : 
• Acetylcholinesterase enzyme cleaves acetylcholine to form acetate and choline and therefore terminates acetylcholine action.
• Disulfiram (Antabuse): Used in treatment of alcoholism, the drug   irreversibly inhibits the enzyme aldehyde dehydrogenase

Exam Question

• The presence of a noncompetitive inhibitor can Lead to a decrease in the observed Vmax
• A competitive inhibitor of an enzyme will Bind to the same site as the substrate
• In competitive inhibition Vmax is unchanged but Km increased
• Disopropyl phosphorofluoridate (DFP) reacts with serine proteases irreversibly and therefore is Non-competitive inhibitor
• In noncompetitive antagonism Km value decreased; V max decreased
• Atropine is useful in organophosphate poisoning because it is a competitive antagonist of acetylcholine
• Non-competitive inhibitor of carbonic anhydrase is Acetazolamide
• Non-depolarizing muscle relaxants are Competitive inhibitor of acetylcholine
• Imatinib and suntinib are competitive inhibitors of tyrosine kinase
• If V max decrease to 80% due to an inhibitor and Km is same as before Non competitive type of inhibition
• Cyanide affects respiratory chain by Non-competitive irreversible inhibition
• Substance which binds to substrate other than catalytic enzyme is Non-competitive inhibitor.