Types of enzyme inhibition
Enzyme inhibition may be of different types such as
(c) non-competitive and
(d) allosteric inhibition.
This type of inhibition occurs when the structure of inhibitor resembles that of the substrate. The inhibitor competes with the proper substrate for binding at the active site of the enzyme. In this type of inhibition, both ES complex and EI complex (enzyme - inhibitor complex) are formed during the reaction. The relative amounts of the two complexes depend partly upon the affinity of the enzyme towards the substrate and inhibitor and partly upon the relative concentration of substrate and the inhibitor. Thus if the inhibitor is present in sufficiently high concentration, it can displace the substrate entirely and thus blocks the reaction completely (Fig.3.5).
Succinate dehydrogenase catalyses the conversion of succinic acid to fumaric acid
This reaction is completely inhibited by malonic acid which has structural resemblence with succinic acid.
- a competitive inhibitor of succinate dehydrogenase
This type of inhibition can be reduced by increasing the concentration of the substrate and for this reason competitive inhibition is called as reversible inhibition. Many competitive inhibitors are used as drugs to block particular metabolic reactions.
In this type of inhibition, the inhibitor combines with enzyme - substrate complex to give an inactive enzyme - substrate - inhibitor complex which cannot undergo further reaction to yield the product (Fig. 3.6).
In this type, the degree of inhibition may increase when the substrate concentration is increased. This inhibition cannot be reversed by increasing the concentration of substrate.
In this type of inhibition, the inhibitor can combine with either the free enzyme or the enzyme substrate complex, interfering with the action of both. Non competitive inhibitor bind to the site on the enzyme other than the active site, often to deform the enzyme, so that it does not form the ES complex at its normal rate and once formed, the ES complex does not decomposes at the normal rate to yield products. These effects are not completely reversed by increasing the substrate concentration (Fig. 3.7).
a. Effect of iodoacetamide on - SH group containing enzymes
b. Effect of diisopropyl phosphofluoridate on acetyl choline esterase.
These two inhibitors completety inactivate the respective enzymes.
This inhibition can be partially reversible.
This type of inhibition is otherwise known as end product inhibition. The inhibitor binds with the modulator binding site (or) allosteric site of the enzyme. The inhibitor present at the allosteric site may affect the conformation at the active site with the result it becomes difficult for the enzyme to take up the substrate molecule, and in the extreme case, the enzyme completely fails to take up the substrate molecule (Fig. 3.8).
This type of inhibition is seen in multistep reactions in which each step is catalysed by different enzymes as shown below.
where A is the starting substrate B,C,D,F are intermediates, a,b,c,d are enzymes and P the product. When the product concentration (P) increases, it binds with the enzyme ‘a’ which is the first enzyme in the reaction sequence. This enzyme which can be inhibited by the end product is known as allosteric enzyme.
when isoleucine production increases, as a regulatory mechanism, it binds with threonine deaminase in the allosteric site and inhibit further binding of the substrate with the enzyme and ultimately production of isoleucine is stopped. This inhibition is otherwise known as feed back inhibition.
Many metabolic reactions in our body are regulated by means of allosteric enzymes.