C1.1.17 Mechanism-based inhibition (HL) Notes

Mechanism-Based Inhibition

1. In a world without antibiotics infections that are now easily treatable could become life-threatening.
2. This was kickstarted by the groundbreaking discovery of penicillin, which works by irreversibly inhibiting a critical bacterial enzyme.

What is Mechanism-Based Inhibition?

1. Unlike reversible inhibitors, which temporarily block enzyme activity, mechanism-based inhibitors form permanent bonds, irreversibly disabling the enzyme.
2. The inhibitor initially binds to the active site of the enzyme, mimicking the natural substrate.
3. Once bound, the inhibitor undergoes a chemical reaction at the active site, forming a covalent bond with the enzyme.
4. This results in irreversible conformational changes, permanently inactivating the enzyme.

Mechanism-based inhibition and Penicillin

1. Penicillin, a widely used antibiotic, is a classic example of a mechanism-based inhibitor.
2. Penicillin targets bacteria by inhibiting the enzyme transpeptidase, which is essential for building strong cell walls.

The Role of Transpeptidase

1. Bacterial cell walls are made of peptidoglycan, a mesh-like structure that provides strength and prevents the cell from bursting.
2. Transpeptidase cross-links peptidoglycan strands, reinforcing the cell wall.
3. Without this enzyme, the cell wall becomes weak and susceptible to lysis (bursting).

Penicillin’s Action

1. Binding to the Active Site: Penicillin mimics the enzyme’s natural substrate and binds to its active site.
2. Formation of a Covalent Bond: Once bound, penicillin forms a covalent bond with a serine residue in the active site, permanently inactivating the enzyme.
3. Inhibition of Cell Wall Synthesis: With transpeptidase disabled, the bacterial cell wall cannot be repaired or expanded, leading to cell lysis and death.

Why is Penicillin So Effective?

Penicillin’s effectiveness lies in its ability to exploit a weakness in bacterial cells.

1. Specificity: It targets transpeptidase, an enzyme not found in human cells, making it safe for human use.
2. Irreversibility: The covalent bond formed between penicillin and the enzyme is permanent, ensuring long-lasting inhibition.
3. Critical Target: By disrupting cell wall synthesis, penicillin attacks a process essential for bacterial survival.

Resistance to Penicillin: The Role of Transpeptidase Mutations

1. While penicillin has saved countless lives, some bacteria have developed resistance.
2. One common mechanism involves mutations in transpeptidase that reduce penicillin’s ability to bind.

How Mutations Confer Resistance

1. Altered Active Site: Mutations change the shape of the enzyme’s active site, preventing penicillin from binding effectively.
2. Preserved Function: Despite these changes, the enzyme retains its ability to cross-link peptidoglycan strands, allowing the bacteria to survive.

Implications of Resistance

1. Reduced Efficacy: Penicillin becomes less effective against resistant strains, requiring alternative treatments.
2. Spread of Resistance: Resistant bacteria can pass these mutations to other strains, making infections harder to treat.