An irreversible inhibitor covalently modifies the active site of an enzyme. Which characteristic distinguishes this from reversible inhibition?

Explanation

## Irreversible vs Reversible Inhibition **Key Point:** Irreversible inhibitors form **covalent bonds** with the enzyme, permanently inactivating it. Reversible inhibitors form **non-covalent interactions** and can dissociate. ### Defining Features of Irreversible Inhibition **High-Yield:** Irreversible inhibition is characterized by: 1. **Covalent bond formation** with enzyme (usually with active site residues) 2. **Permanent inactivation**—dialysis cannot restore activity 3. **Time-dependent kinetics**—inhibition increases with time 4. **Cannot be overcome** by increasing substrate concentration 5. **Stoichiometric** relationship (1 inhibitor molecule = 1 enzyme molecule inactivated) ### Mechanism of Covalent Modification Common targets in irreversible inhibition: - **Serine proteases:** Organophosphates and carbamates covalently phosphorylate active site serine (acetylcholinesterase) - **Cysteine residues:** Alkylating agents form thioether bonds - **Histidine residues:** Diethylpyrocarbonate (DEPC) carbamoylates histidine - **Lysine residues:** Succinic anhydride acetylates amino groups ### Reversible vs Irreversible Comparison | Property | Reversible | Irreversible | |----------|-----------|---------------| | **Bond Type** | Non-covalent (H-bonds, electrostatic, van der Waals) | Covalent | | **Dialysis Restores Activity** | Yes | **No** | | **Substrate Overcomes Inhibition** | Yes (competitive only) | No | | **Time-Dependent** | No | Yes | | **Kinetics** | Follows Michaelis-Menten | Follows first-order decay | | **Examples** | Competitive: methotrexate; Non-competitive: heavy metals | Penicillin, aspirin, cyanide | **Mnemonic:** **COVALENT = Cannot Overcome, Voids Activity, Lasting Effect, Enzyme Neutralized, Non-dialyzable, Time-dependent** ### Clinical Pearl **Aspirin** irreversibly acetylates serine 529 in platelet cyclooxygenase (COX-1), preventing thromboxane A~2~ synthesis for the platelet's lifespan (~7–10 days). This is why aspirin's antiplatelet effect persists even after the drug is cleared from circulation—the enzyme cannot be restored until new platelets are synthesized. **Warning:** Do not confuse irreversible inhibition with **non-competitive inhibition**. Non-competitive inhibitors are usually reversible; irreversible inhibitors are a separate category defined by covalent bonding.