General Process Overview
Unlike reversible processes, in irreversible inhibition, the inhibitor molecule binds permanently to the enzyme. A stable complex is formed, described by the simple equation:
`E + I → E-I`
The main feature of this interaction is that the catalytic activity of the enzyme is no longer restored. The protein is permanently inactivated. Depending on exactly where the blocking substance attaches, two types of irreversible inhibitors are distinguished: specific and nonspecific.
Specific irreversible inhibitors
These substances act with maximum precision: they block strictly defined functional groups located exclusively within the active site of the enzyme.
A classic example of such a substance is diisopropyl fluorophosphate (DFP). It belongs to the group of specific inhibitors of so-called "serine" enzymes, a prominent representative of which is chymotrypsin.
Mechanism of action of DFP:
- The inhibitor penetrates the active site of the enzyme.
- It finds the hydroxyl group (-OH) belonging to the amino acid serine (this particular residue takes direct part in catalysis).
- It forms a strong covalent bond with it, releasing hydrogen fluoride.
The reaction scheme is as follows: > Enzyme-CH₂-OH + DFP → Enzyme-DFP + HF
As a result, inactive diisopropylphosphoryl-chymotrypsin is formed. The catalytic activity of the enzyme drops to zero, as the key participant in the reaction — serine — is securely blocked.
Nonspecific irreversible inhibitors
Unlike specific agents, nonspecific inhibitors are not limited to the active site. They form covalent bonds with specific chemical groups at any site of the protein molecule.
A typical representative of this group is iodoacetate. Its targets are sulfhydryl groups (-SH) belonging to cysteine residues.
Mechanism of action of iodoacetate:
- The reagent attacks any accessible SH groups of proteins, regardless of whether they are located in the active site or on the periphery of the molecule.
- Covalent modification (S-alkylation) occurs, accompanied by the release of hydrogen iodide.
- Massive changes in the structure of side chains lead to disruption of the conformation of the entire enzyme molecule.
Reaction scheme: > Enzyme-CH₂-SH + Iodoacetate → Acetylated enzyme (S-linked) + HI
Changes in the spatial structure of the molecule inevitably entail deformation of the active site. As a consequence, affinity for the substrate may decrease, and the final result is a pronounced decrease in the catalytic activity of the enzyme.
Briefly: answers to topical questions
Which well-known medications act via the mechanism of irreversible inhibition?
Well-known medications that act via irreversible inhibition include aspirin and nialamide.
- Aspirin — irreversibly inhibits the enzyme cyclooxygenase by acetylating a serine residue in its active site, which blocks the production of prostaglandins and thromboxanes.
- Nialamide — causes irreversible inhibition of monoamine oxidase by forming stable covalent bonds with the functional groups of the enzyme's active site.
Which group of poisons does diisopropyl fluorophosphate belong to, and what symptoms does its poisoning cause?
Diisopropyl fluorophosphate belongs to the group of organophosphorus inhibitors and is classified as a specific inhibitor of "serine" enzymes. Upon poisoning, this substance forms covalent bonds with acetylcholinesterase, irreversibly blocking its activity. This leads to an increase in the amount of acetylcholine in the synaptic cleft because it is no longer degraded. Physiologically, such an excess of the neurotransmitter causes increased contraction of smooth muscles, which manifests as spasms.
Which heavy metals can act as nonspecific irreversible inhibitors?
Cations of heavy metals such as mercury, lead, and copper can act as nonspecific irreversible inhibitors. They inactivate virtually any enzyme by causing protein denaturation. Ions of these metals (particularly lead and mercury) interact with the sulfhydryl groups of enzymes, forming stable compounds that lead to chemical modification and loss of catalytic activity, and ultimately to the blockade of various enzyme systems in the body.
Specific DFP hits the target precisely (the OH group of serine in the active site), while nonspecific iodoacetate "shoots" at all available SH groups of cysteine in the molecule.
Class and exam questions
Why cannot irreversible inhibition be reversed?
Because a strong covalent bond is formed between the inhibitor and the functional groups of the enzyme, which cannot be broken under normal physiological conditions.
How does a specific inhibitor differ from a nonspecific one?
A specific inhibitor binds strictly to certain groups in the active site of the enzyme. A nonspecific inhibitor interacts with suitable groups (e.g., SH groups) across the entire surface of the protein molecule.
Which enzyme is inhibited by diisopropyl fluorophosphate (DFP)?
DFP inhibits "serine" enzymes, such as chymotrypsin. It binds to the OH group of serine in the active site.
What else to study on this topic
- Structure and mechanism of action of chymotrypsin
- Structural features of the active site of serine proteases
- The role of sulfhydryl (SH) groups of cysteine in the tertiary structure of proteins
- The effect of conformational changes on enzyme activity
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