Enzyme Inhibition

Enzyme inhibiton

The enzymatic reaction may be altered by a moderator. In some cases, the enzyme action can be reduced or inhibited and in some other cases the action can be enhanced. If the effect is to reduce the rate, and this is called inhibition and enhanced it is called activation. Inhibitors are molecules, which inhibit or antagonize the actions of Enzymes, thereby inhibiting the enzyme catalyzed reaction. The reduced enzymatic rate due to change in pH, temperature etc is not considered as inhibition. Inhibition is broadly classified as two major types. Irreversible and reversible inhibition.

Reversible Inhibition

Here the enzyme action can be reversed even after the inhibition. Usually the compound or the inhibitor binds to the enzyme by weak interactions. No covalent bond occurs here. Reversible inhibitors are classified into competitive, noncompetitive and uncompetitive.

Competitive inhibition

Competitive inhibitors bind only to free enzyme molecules.


Here the inhibitors are structurally similar to the substrate and therefore inhibitors will bind to the active site or substrate binding site of the enzyme. Once bound the enzyme cannot convert the inhibitor to produce the products. The inhibition can be reversed by increasing the concentration of the substrate.  Since both substrate and the enzyme have structural similarity, competition for the binding site occurs. More substrate will replace the noncovalently bond inhibitor from the active site of enzyme thereby the reaction proceeds to form the product.






Examples for competitive inhibition

      

LB plot for competitive inhibition

Here Km increases but there is no change is Vmax. Km for the substrate shows a slight increase in presence of inhibitor and can be seen in LB plot as a shift in x intercept (-1/Km) and in the slope of line Km/Vmax.

 

Examples

Arsenate is structurally and chemically similar to phosphate (Pi). Therefore, it acts as a competitive inhibitor. Glyceraldehyde 3 phosphate dehydrogenase. If arsenic is there arseno 3 phosphoglycerate instead of 1, 3 bisphosphoglycerate.

Many drugs are also competitive inhibitors. Eg: Sulfanilamide acts as a competitive inhibitor for para amino benzoic acid in folic acid synthesis of bacteria.

Noncompetitive Inhibition

Here the inhibitor binds at a site other than substrate binding site. Here there is no substrate analogy. Binding of inhibitor prevents the substrate from binding to the active site of enzyme or it will inhibit the ES complex. Inhibition is not reversed by increasing the concentration of the substrate. Inhibitor can form both binary (EI) and ternary (ESI) complexes and are therefore dead-end complexes. Here Vmax decreases but there is no change in Km. Inhibition can be reversed by extensive dialysis if inhibitor has not covalently reacted with the substrate.

Reaction mechanism


     Adapted from Mcstrother derivative work of Comp_inhib.svg by User:Srhat - Allosteric_comp_inhib_1.svg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12101389

LB plot for noncompetitive inhibition

Examples

In glycolysis, Phosphoenol pyruvate is converted to pyruvate by the enzyme pyruvate kinase. Alanine is an amino acid which is synthesized from pyruvate also inhibits the enzyme pyruvate kinase during glycolysis. Alanine is a non-competitive inhibitor;therefore, it binds away from the active site to the substrate in order for the production of alanine.

Another example of non-competitive inhibition is given by glucose-6-phosphate inhibiting hexokinase in the brain

Uncompetitive inhibition

Uncompetitive inhibition, also called anti-competitive inhibition. This type of inhibition takes place when the inhibitor binds to Enzyme–substrate complex. Uncompetitive inhibition typically occurs in reactions with two or more substrates or products. In uncompetitive inhibition inhibitor binds to a site which only becomes available when the substrate (Sx) binds to the active site of enzyme. This inhibitor usually occurs in multisubstrate reaction whereby the inhibitor is competitive to one substrate (Sy) and uncompetitive to the other substrate (Sx).

 

 Here inhibition is more seen at high substrate concentrations and cannot be overcome as Km and Vmax is reduced. In uncompetitive inhibition, increasing amount of substrate will not make any change in the inhibition. This type of inhibition gives parallel line in LB plot. Therefore LB plot is usually used to distinguish between these three inhibitions.

Competitive inhibition: LB plot intercept at a common point on y axis

Non competitive inhibiton: LB plot intercept at a common point behind y axis

Uncompetitive inhibition: LB plot will be given as parallel lines.

Adapted from Sponk (talk) - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11936052

 

LB plot for uncompetitive inhibition

Reaction mechanism

Comments

Post a Comment

Popular posts from this blog

Enzyme Kinetics

Image
A ctivation Energy Activation energy is the amount of energy required to bring the reactant molecules to a higher energy level (activated state) where a chemical bond may be formed or broken to form product or products. Like chemical catalysts, enzymes accelerate the rate of biochemical reactions by lowering the activation energy. When the reactant molecules reach this activated condition, they are energy-rich and are in a transition state. In enzyme reactions, the enzyme-substrate complex represents the transition state. The enzyme functions to lower the amount of energy required to bring the substrate to the transition state. An example may be cited to explain the significance of activation energy. A mixture of hydrogen and oxygen will remain unchanged indefinitely, although they have the ability to combine producing water. An electric spark will bring them to the transition state and they combine with release of energy. Here, the electric spark provides the activation energy. T
Read more

Nomenclature and Classification of Enzymes

Image
Nomenclature and Classification of Enzymes Enzymes were classified and named earlier based on different features. Most enzymes have been named by adding the suffix ‘ ase ’ to the name of their substrate or to a word or phrase describing their activity. Thus, urease catalyse the hydrolysis of urea and lipase helps in the hydrolysis of lipids. Enzymes were also named by their discoverers for a broad function           Eg : pepsin. In greek ‘ pepsis ’ means digestion and lysozyme was named for its ability to lyse (meaning breakdown) bacterial cell walls Enzymes were also named based on their source           E g : trypsin which came from Greek tryein means to wear down and the enzyme was                   obtained by rubbing pancreatic tissue with glycerine. Next naming is two word naming. Eg : pyruvate decarboxylase, First word indicates the substrate and the second word represents the reaction which is catalysed. Sometimes the same enzyme has two or more names or two enzym
Read more