Sajith Jayasinghe
TUTORIALS: Visualizing the Inhibition of Cyclooxygenase by Aspirin
Aspirin is an non-steroidal anti-inflammatory drug (NSAID) that also exhibits, among others, analgesic (pain reducer) and anti-pyretic (fever reducer) functions. The mode of action of aspirin appears to be the inhibition of the formation of protaglandins, a group of lipid molecules with hormone-like action. Prostaglandins are 20 carbon fatty acids that that exhibit a variety of physiological effects including: the production of the inflammatory response, the production of pain, the regulation of body temperature, the regulation of platelet aggregation, and the regulation of blood vessel constriction. Prostaglandins are synthesized by the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) which catalyze the conversion of arachidonic acid (a fatty acid component of lipid membranes) to prostaglandins. Aspirin binds to the active site of these enzymes inhibiting the synthesis of prostaglandins.
In this tutorial we will examine the structure of COX-1 with a bound aspirin analog.
(1). into the JSMol window (left).
Rotate the molecule around and observe the distribution of secondary structures.
The funtional unit of COX-1 is a dimer.
(2).
The crystal structure of COX-1 has a bound salicylic acid molecule in its active site. This salicylic acid molecule is generated when acetyl salicylic acid (aspirin) acetylates an active site serine residue. This acetylation inactivates COX-1 preventing the synthesis of prostaglandins and is responsible for the observed therapeutic effects of aspirin.
(3).
Rotate the molecule and observe the relative orientations of the salicylic acid and the serine-530.
The acetylation of serine-530 by acetyl salicylic acid is aided by residues 120 and 355.
(4).
The active site of COX-1 also contains several hydrophobic residues (such as Ile-523, Ala-527, and Val-349) that aid in the binding of acetylsalicylic acid and other NSAIDs such as ibuprofen and acetaminophen.
(5).