Question

Explain how aspirin recognizes and binds to its target protein, cyclooxygenase?

Answer 1

Cyclooxygenases or COX are enzymes involved in the production of prostaglandins and thromboxane involved in inflammation from arachidonic acid. Aspirin acts by suppressing the synthesis of prostaglandins and thromboxanes by binding to COX enzymes. COX enzyme is classified as a serine protease in which serine amino acid residue located in the active site of the enzyme contribute towards its biological function. COX is found everywhere in th body and during inflammatory process COX will be over expressed. Aspirin acts as an acylating agent and the acetyl group of the drug will covalently binds with the hydroxyl group of the catalytic serine residue (amino acid number 529) of COX enzyme through acylation reaction. The binding of aspirin at the active site of COX causes a steric hindrance for the binding of the substrate arachidonic acid and thereby the production of prostaglandins and thromboxane are inhibited. Because of the formation of covalent bond, the binding of Aspirin to COX is irreversible. COX enzyme exists in two isoforms namely, COX-1 and COX-2. COX-1 is present in platelets, mucosal cells of GI tract, and in the renal tubules. COX-2 enzyme is present in the endothelial cells, macrophages, mesangial cells, fibroblasts and chondrocytes. Aspirin is non-selective, thus it is able to inhibit both the isoforms irreversibly by binding to the active site serine residue.