The main difference between reversible and irreversible enzyme inhibition is that reversible enzyme inhibition inactivates enzymes through noncovalent interactions. In contrast, irreversible enzyme inhibition inactivates enzymes through covalent inactivation of the active site. Furthermore, the inhibition effect is reversible in the reversible enzyme inhibition, but the inhibition effect is irreversible in the irreversible enzyme inhibition.
In brief, reversible and irreversible enzyme inhibition are the two methods of enzyme inhibition mechanisms responsible for decreasing the enzyme activity. Generally, inhibitors reduce the compatibility of substrate and enzyme, leading to the inhibition of enzyme-substrate complexes’ formation.
Key Areas Covered
1. What is Reversible Enzyme Inhibition
– Definition, Process, Types
2. What is Irreversible Enzyme Inhibition
– Definition, Process, Types
3. What are the Similarities Between Reversible and Irreversible Enzyme Inhibition
– Outline of Common Features
4. What is the Difference Between Reversible and Irreversible Enzyme Inhibition
– Comparison of Key Differences
Key Terms
Competitive Inhibitors, Covalent, Irreversible Enzyme Inhibition, Noncompetitive Inhibitors, Noncovalent, Reversible Enzyme Inhibition, Uncompetitive Inhibitors
What is Reversible Enzyme Inhibition
Reversible enzyme inhibition is a type of enzyme inhibition in which inhibitor molecules bind to the enzyme through non-covalent interactions. Here, these interactions include hydrogen bonds, hydrophobic interactions, and ionic bonds. However, reversible inhibitor molecules do not undergo chemical reactions with the amino acid residues of the active site of the enzyme. Hence, reversible inhibitors can be removed from the enzyme either through dilution or dialysis.
Figure 1: Competitive Inhibition – DHFR Methotrexate Inhibitor
Furthermore, the four types of reversible enzyme inhibitors are competitive, non-competitive, uncompetitive, and mixed inhibitors. Of these, competitive inhibitors are the compounds with structural resemblance to the substrate of a particular enzyme. Hence, it competes with the substrate for achieving the active site of the enzyme, reducing the enzymatic action. In contrast, non-competitive inhibitors bind to the enzyme or enzyme-substrate complex at a site other than the active site. Still, this may alter the 3D-conformation of the enzyme, which in turn reduces the enzyme function.
Figure 2: Types of Reversible Enzyme Inhibition
Meanwhile, uncompetitive inhibitors bind to the enzyme-substrate complex, effectively eliminating the enzyme-substrate complex, and thus, reducing the product formation. On the other hand, mixed inhibitors can bind to both enzyme and enzyme-substrate complex, releasing the substrate from the forming enzyme-substrate-inhibitor complex. On the contrary to the mixed inhibitors, non-competitive inhibitors do not allow the dissociation of the substrate from the forming enzyme-substrate-inhibitor complex.
What is Irreversible Enzyme Inhibition
Irreversible enzyme inhibition is the second type of enzyme inhibition with permanent inhibitory effects. Also, the main significant feature of the irreversible enzyme inhibitors is that they covalently bind to the amino acid residues of the active site of the enzyme. On that account, this type of inhibitors bears reactive functional groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates. Significantly, these reactive groups are nucleophilic and form covalent adducts with the amino acid side chains in the active site.
Figure 3: Reaction of the Irreversible Inhibitor Diisopropylfluorophosphate (DFP) with a Serine Protease
As an example, nerve gases, especially DIFP, irreversibly inhibit biological systems by forming an enzyme-inhibitor complex. Usually, it occurs through a specific OH group of serine at the active sites of certain enzymes. Typically, peptidases such as trypsin and chymotrypsin contain serine groups at the active site that can be inhibited by DIFP. Consequently, this type of covalent modifications of the active site of the enzyme may lead to the permanent inactivation of the enzyme and the enzymatic action is difficult to recover by the addition of excess substrate to the medium.
Similarities Between Reversible and Irreversible Enzyme Inhibition
- Reversible and irreversible enzyme inhibition are two types of enzyme inhibition mechanisms.
- They are responsible for reducing the activity of the enzyme.
- Usually, they reduce the compatibility of the enzyme to its substrate, inhibiting the formation of the enzyme-substrate complex.
- During inhibition, inhibitor molecules bind to the enzyme either temporarily or permanently.
- Naturally, enzyme inhibition helps to regulate metabolism. Also, many drug molecules are enzyme inhibitors.
Difference Between Reversible and Irreversible Enzyme Inhibition
Definition
Reversible enzyme inhibition refers to the process of binding inhibitors to the enzyme through noncovalent interactions so that, once removed, they allow the restoring of the enzyme function. Meanwhile, irreversible enzyme interaction refers to the process of binding inhibitors to the enzyme through covalent interactions so that, their dissociation takes a long time, permanently removing the enzyme action.
Type of Inhibitor Binding
In reversible enzyme inhibition, inhibitors bind through non-covalent interactions such as hydrogen bonds, hydrophobic interactions, and ionic bonds. In contrast, in irreversible enzyme inhibition, inhibitors bind through covalent interactions, which modify amino acid residues by reactive functional groups.
Dissociation of the Enzyme-Inhibitor Complex
In reversible enzyme inhibition, the enzyme-inhibitor complex dissociates quickly, but the enzyme-inhibitor complex dissociates very slowly in the irreversible enzyme inhibition.
Restoring the Inhibition
Reversible enzyme inhibition can be restored, but irreversible enzyme inhibition takes a long time to restore.
Types
Four types of reversible enzyme inhibition are competitive, uncompetitive, non-competitive, and mixed inhibition, while irreversible enzyme inhibition occurs through the covalent inactivation of the active site of the enzyme.
Examples of Inhibitors
Some of the examples of reversible enzyme inhibitors include DHFR, antiviral drugs such as ritonavir, oseltamivir, and tipranavir, etc. Meanwhile, some of the examples of irreversible enzyme inhibitors include DFP, DFMO, insecticides such as malathion, herbicides such as glyphosate, and disinfectants such as triclosan, etc.
Conclusion
Reversible enzyme inhibition is the process of inhibiting the action of an enzyme temporarily. Therefore, with the removal of the inhibitory action, the function of the enzyme can be restored. Also, reversible inhibitors bind to the enzyme through non-covalent interactions. Hence, it permits the quick dissociation of the enzyme-inhibitor complex, restoring the enzyme function. In contrast, irreversible enzyme inhibition is the process of permanently inhibiting the enzyme function. Therefore, the dissociation of the enzyme-inhibitor complex takes a long time. Furthermore, inhibitor molecules covalently bind to the residues of the active site of the enzyme, blocking the formation of the enzyme-substrate complex. On these accounts, the main difference between reversible and irreversible enzyme inhibition is the mechanism of binding of the inhibitors to the enzyme and the consequent effects.
References:
1. “18.8 Enzyme Inhibition.” The Basics of General, Organic, and Biological Chemistry, vol. 1.0. Available Here.
Image Courtesy:
1. “DHFR methotrexate inhibitor” By Thomas Shafee – Own work (CC BY 4.0) via Commons Wikimedia
2. “Types of inhibition en” By fullofstars – en:Image:Inhibition.png (PD) (Public Domain) via Commons Wikimedia
3. “DIF reaction” By TimVickers – Own work (Public Domain) via Commons Wikimedia
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