Principles of Biochemistry

8.2.3.6.1. Competitive inhibitors

Competitive inhibitors usually resemble the normal substrate in three - dimensional structure. The competitive inhibitor I, simply combine reversibly with the enzyme to form an EI complex

E + I → EI

However, the inhibitor I cannot be attacked by the enzyme to form new reaction products.

E.g. Competitive inhibition of succinate dehydrogenase by the malonate.

This enzyme catalyzes the removal of two hydrogen atoms from each of the two methylene (-CH2 -) groups of succinate to form fumerate. Succinate dehydrogenase is inhibited by malonate, which resembles succinate in having two ionized carboxyl groups pH 7.0 but differs in having only three carbon atoms. However, malonate is not dehydrogenated by succinate dehydrogenase ; it simply occupies the active site keeping it from acting on its normal substrate The inhibition by malonate can be reversed by increasing the concentration of succinate

CH2-COOH Succinate Dehydrogenase CH-COOH

| + FAD → || + FADH₂

CH2-COOH HOOC-HC

Succinate Fumerate

Another compound that may act as competitive inhibitors of succinate dehydrogenase is oxaloacetate. From this structural relationship it has been concluded that the catalytic site of succinate dehydrogenase has two appropriately spaced positively charged groups capable of attracting the two negatively charged carboxylate groups of the succinate anion. The catalytic site of succinate dehydrogenase thus shows complementary to the structure of its substrate.