Mechanism-Based Inhibition
- In a world without antibiotics infections that are now easily treatable could become life-threatening.
- This was kickstarted by the groundbreaking discovery of penicillin, which works by irreversibly inhibiting a critical bacterial enzyme.
What is Mechanism-Based Inhibition?
Definition
Mechanism-based inhibition
Mechanism-based inhibition, also called suicide inhibition, occurs when an inhibitor binds irreversibly to the active site of an enzyme and causes chemical changes that permanently deactivate the enzyme
- Unlike reversible inhibitors, which temporarily block enzyme activity, mechanism-based inhibitors form permanent bonds, irreversibly disabling the enzyme.
- The inhibitor initially binds to the active site of the enzyme, mimicking the natural substrate.
- Once bound, the inhibitor undergoes a chemical reaction at the active site, forming a covalent bond with the enzyme.
- This results in irreversible conformational changes, permanently inactivating the enzyme.
This type of inhibition is also called suicide inhibition because the enzyme effectively "destroys" its own activity by interacting with the inhibitor.
Mechanism-based inhibition and Penicillin
- Penicillin, a widely used antibiotic, is a classic example of a mechanism-based inhibitor.
- Penicillin targets bacteria by inhibiting the enzyme transpeptidase, which is essential for building strong cell walls.
The Role of Transpeptidase
- Bacterial cell walls are made of peptidoglycan, a mesh-like structure that provides strength and prevents the cell from bursting.
- Transpeptidase cross-links peptidoglycan strands, reinforcing the cell wall.
- Without this enzyme, the cell wall becomes weak and susceptible to lysis (bursting).
Penicillin’s Action
- Binding to the Active Site: Penicillin mimics the enzyme’s natural substrate and binds to its active site.
- Formation of a Covalent Bond: Once bound, penicillin forms a covalent bond with a serine residue in the active site, permanently inactivating the enzyme.
- Inhibition of Cell Wall Synthesis: With transpeptidase disabled, the bacterial cell wall cannot be repaired or expanded, leading to cell lysis and death.
