Structural Biochemistry/Enzyme/Irreversible Inhibitor
Irreversible inhibitors are covalently or noncovalently bound to the target enzyme and dissociates very slowly from the enzyme. There are three types of irreversible inhibitors: group-specific reagents, reactive substrate analogs also known as affinity labels and suicide inhibitors.
- Group specific reagents react with specific amino acid side chains like diisopropylphosphofluoridate (DIPF) and iodoacetamide. For example, only 1 of the 28 serine residues in chymotrypsin is modified by DIPF. This means that this specific residue is especially reactive; moreover, it is implied that this specific residue lies in the active site of the enzyme chymotrypsin. DIPF has also provided data that suggests, through its binding with active serine residues, that there is indeed a reactive serine residue contained within the active site of the enzyme Acetylcholinesterase. The inactivating functionality of DIPF and similarly-shaped molecules in acetylcholinesterase is representative of a group of compounds, known as nerve agents.
- Affinity labels (Reactive substrate analogs) are structurally similar to the substrate that can covalently bind to the active site and are therefore more specific than group specific reagents. An example is Tosyl-L-phenylalanine chloromethyl ketone (TPCK) which is an analog for chymotrypsin which binds to the active site and reacts irreversibly with the histidine residue to inhibit the enzyme. Another example is triose phophate isomerase which mimics the substrate and binds covalently to the active site and then modifying the enzyme so it becomes irreversibly inhibited.
- Suicide inhibitors (Mechanism-based inhibitors) bind to the enzyme as a substrate and is processed by a normal catalytic mechanism that generates a chemically reactive intermediate that inactivates the enzyme through covalent modification. An example of a mechanism-based inhibitor can be seen through the inhibitory power of the planar proline intermediate formed during proline racemization. During this process, a trigonal intermediate is formed, and the formation of the racemase is inhibited because the tetrahedral intermediate necessary for formation of the product is not formed. The isomerization of proline through the planar transition state underscores the essence of transition-state analogs as potent inhibitors of enzymes.
Irreversible inhibition is covalent modification of enzymes such that the chemical reaction is not reversible; the inhibition molecules has specificity for their own enzyme to inactivate them, such that they work by changing active site of enzymes; the binding of enzyme to inhibitor forms enzyme complex that is reversible and not covalent that reacts to form another complex that can not work for catalysis reaction. The inhibition reaction can be changed by reversible competition of enzyme and substrate or other reversible inhibitor.
 Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007: 229.