Enzyme Inhibitors

Enzyme Inhibitors are the molecules that make the interaction(temporary or permanent) with the enzyme to reduce the catalytic activity of the enzyme and prevent enzymes from behaving normal manner. Enzymes are protein molecules that facilitate speed-up chemical reactions and convert substrate to product. Inhibitors interact with the enzyme to stop or inhibit this activity by binding to the active site(prevent substrate from binding) or the other site on the enzyme to reduce catalytic activity.

Inhibitors play crucial roles in regulating metabolic pathways, and controlling enzyme function, and are used extensively in research, medicine, and industry for therapeutic, diagnostic, and biotechnological purposes.

Types of inhibitors

There are two main types of enzyme inhibitors based on their mechanism of action and effects on enzyme activity. these are Reversible and irreversible inhibitors.

Reversible inhibitors

Reversible inhibitors make interactions with enzymes through non-covalent linkages or weak interactions which can be reversed. Reversible inhibitors include Competitive, Non-competitive, Uncompetitive, and Mixed Inhibitors.

Competitive Inhibitors

Competitive inhibitors resemble the substrate in structure and compete with the substrate to bind to the active site. This inhibition can be overcome by increasing the concentration of substrate, in this way the chances of inhibitor binding to the active site decrease.

For. Example

In the citric acid cycle, Malonate (inhibitor) inhibits (stops activity) of succinate dehydrogenase (enzyme).an enzyme that plays a crucial role in both the citric acid cycle (also known as the Krebs cycle) and the electron transport chain in mitochondria.

Non-competitive Inhibitors

Non-competitive inhibitors interact with the enzyme other than the active site this makes conformational changes in the enzyme molecule that prevent the binding of substrate to the enzyme that reduces its activity.

For. Example

In glycolysis, ATP (inhibitor) can inhibit phosphofructokinase (enzyme).which is a key regulatory enzyme in this metabolic pathway. This means that as ATP levels rise within the cell, ATP molecules can bind to specific allosteric sites on phosphofructokinase. This binding alters the enzyme’s conformation, reducing its activity. As a result, glycolysis slows down when ATP levels are high.

Uncompetitive Inhibitors

The Uncompetitive Inhibitors do not bind to the free enzyme, it makes attachment with the enzyme-substrate complex. they prevent enzymes from converting substrate into products. So in his way, they block the activity of enzymes. This type of inhibition is a rare case.

For. Example

Fluoride ion (inhibitor) inhibits enolase.

Fluoride ion is known to inhibit the enzyme enolase, which plays a crucial role in glycolysis by catalyzing the conversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP). Enolase is a metalloenzyme that requires divalent metal ions (such as magnesium or manganese) for its catalytic activity. Fluoride ion inhibits enolase by disrupting this metal ion requirement.

Hydrazine (inhibitor) inhibits aryl sulphatase.

Hydrazine is known to irreversibly inhibit the enzyme aryl sulfatase. Aryl sulfatases are enzymes that catalyze the hydrolysis of sulfate ester bonds in aryl sulfates, which are involved in various physiological processes, including the metabolism of sulfated compounds.

Mixed Inhibitors

The Mixed inhibitors can bind both to the free enzyme or enzyme that is already bound to the enzyme (enzyme-substrate complex). However, they do not follow the route of competitive or non-competitive inhibition.

For. Example

Many drugs act as mixed inhibitors, affecting enzyme activity in various ways.

Irreversible inhibitors

Irreversible Inhibitors make covalent bonds to the enzyme and block the enzyme activity permanently. Irreversible inhibitors typically undergo a chemical reaction with specific amino acid residues or cofactors within the active site or binding site of the target molecule. This reaction can involve nucleophilic attack by residues such as cysteine, serine, or lysine, leading to the formation of a covalent bond between the inhibitor and the target. Once this bond is formed, the inhibitor cannot easily dissociate from the target, resulting in sustained inhibition of enzyme activity.

For. Example

Penicillin and cyanide are common examples of irreversible Inhibitors.

Active-site-directed Irreversible Inhibitors

Active-site-directed irreversible inhibitors (ASDIs) are inhibitors which permanently deactivate enzymes by forming a covalent bond with amino acid residues within the enzyme’s active site. This irreversibly blocks the enzyme’s catalytic activity, making ASDIs valuable tools in both research and drug development.

For. Example

aspirin (acetylsalicylic acid)

Aspirin irreversibly inhibits the enzyme cyclooxygenase (COX), which is involved in the synthesis of prostaglandins, lipid mediators that play a role in inflammation, pain, and fever.

Suicide Inhibitors

Suicide inhibitors, also known as mechanism-based inhibitors or irreversible enzyme inhibitors, that irreversibly bind to enzymes by undergoing a chemical reaction within the enzyme’s active site. This binding effectively “kills” or inactivates the enzyme, hence called them “suicide” inhibitor.

For. Example

Penicillin: β-lactam antibiotics such as penicillin irreversibly inhibit bacterial transpeptidase enzymes (also known as penicillin-binding proteins or PBPs) involved in cell wall synthesis.

Mechlorethamine: Mechlorethamine (mustine) is a nitrogen mustard alkylating agent used in cancer chemotherapy. It acts as a suicide inhibitor by forming covalent bonds with DNA, particularly at guanine residues. This covalent modification interferes with DNA replication and transcription, leading to cell death.

MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that is converted by monoamine oxidase B (MAO-B) in glial cells of the brain into the toxic metabolite MPP+. MPP+ is then taken up by dopaminergic neurons and selectively inhibits mitochondrial complex I, leading to ATP depletion and cell death. This mechanism is implicated in Parkinson’s disease.