Irreversible enzyme inhibitors can be categorized based on their reactive functional groups and mechanisms of action, but a broader classification focuses on their binding properties and how they modify the enzyme.
Types of Irreversible Enzyme Inhibitors
While often categorized by their reactive functional groups (like those listed below), a more helpful way to understand irreversible inhibitors is by how they bind and affect the enzyme.
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Mechanism-Based Inhibitors (Suicide Inhibitors): These are unreactive compounds that are converted by the enzyme's normal catalytic mechanism into a reactive form that then covalently modifies the enzyme, leading to inactivation. Essentially, the enzyme "commits suicide" by activating its own inhibitor. A classic example is allopurinol, used to treat gout. It's converted by xanthine oxidase into a form that irreversibly inhibits the enzyme.
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Affinity Labels (Active Site-Directed Inhibitors): These inhibitors are structurally similar to the enzyme's substrate and bind to the active site. They contain a reactive group that then forms a covalent bond with a residue in the active site, permanently inactivating the enzyme. An example includes reagents that modify specific amino acid residues in the active site.
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Non-Specific Irreversible Inhibitors: These inhibitors are less selective and can react with various amino acid side chains in the enzyme, not just those in the active site. They often cause significant conformational changes in the enzyme, leading to irreversible inactivation. Examples include strong oxidizing or alkylating agents.
Common Reactive Functional Groups in Irreversible Inhibitors
These are the chemical moieties responsible for forming the covalent bonds with the enzyme. The presence of these groups makes the inhibitors highly reactive with enzyme residues.
- Nitrogen Mustards: Alkylating agents that can crosslink DNA and proteins.
- Aldehydes: React with amine groups in proteins to form Schiff bases.
- Haloalkanes: Alkylating agents that can react with various nucleophilic groups.
- Alkenes: Can undergo addition reactions with nucleophilic groups.
- Michael Acceptors: React with nucleophiles via Michael addition.
- Phenyl Sulfonates: React with hydroxyl groups.
- Fluorophosphates: Inhibit serine proteases by reacting with the serine hydroxyl group. (e.g., nerve gases like Sarin)
Characteristics of Irreversible Inhibitors
- Covalent Bond Formation: They form strong, stable covalent bonds with the enzyme.
- Permanent Inhibition: The inhibition is typically permanent, unless the enzyme is degraded and resynthesized.
- Time-Dependent Inhibition: The degree of inhibition increases with time as more inhibitor binds to the enzyme.
- Loss of Enzyme Activity: Results in a permanent loss of catalytic activity.
