Aspirin irreversibly inhibits the enzyme COX2 by transferring an acetyl group to a serine residue at the enzyme active site. However, aspirin has the negative side effect of also inhibiting a related enzyme, COX1, which results in severe Gl distress. An aspirin analog (Q), shown below, was found to be 75 times more selective as an inhibitor of COX2, which suggests that Q could offer the same anti-inflammatory effects of aspirin without the stomach bleeding side effects. a. Draw the structure of the inactivated COX2 enzyme-inhibitor complex with Q. b. What type of bisubstrate mechanism does this inhibitor comple
The Correct Answer and Explanation is:
a. Structure of the Inactivated COX2 Enzyme-Inhibitor Complex with Q
Since the specific chemical structure of inhibitor Q is not shown in the prompt, we will base our answer on a general principle of how aspirin-like molecules inhibit COX2 (cyclooxygenase-2). Aspirin irreversibly inhibits COX enzymes by acetylating a serine residue in the active site, typically Ser530.
In the case of the analog Q, which is more selective for COX2, the structure would still contain an acetyl group or a similar electrophilic moiety capable of covalently modifying the serine hydroxyl group. Thus, the inactivated COX2–Q complex structure would contain:
- The COX2 enzyme, with a serine side chain modified through covalent attachment of part of the inhibitor Q.
- The acetyl or reactive group from Q forms a covalent bond with the hydroxyl oxygen of Ser530, producing an ester linkage.
- The rest of the Q molecule remains bound near the active site, stabilized by non-covalent interactions, such as hydrogen bonding or hydrophobic interactions, depending on its structure.
This complex is irreversible, meaning the enzyme can no longer catalyze the conversion of arachidonic acid to prostaglandins.
b. Type of Bisubstrate Mechanism
A bisubstrate reaction involves two substrates interacting with an enzyme. In this case, the two functional components are:
- The enzyme COX2, which normally binds arachidonic acid.
- The inhibitor Q, which mimics or competes with the normal substrate and forms a covalent intermediate.
The mechanism here is best described as a “ping-pong” (double displacement) bisubstrate mechanism:
- In a ping-pong mechanism, one substrate binds and modifies the enzyme, forming a covalently modified enzyme intermediate.
- The first product (here, possibly leaving group of Q) is released.
- Then the second substrate (in catalysis, this would be O₂ or another reactant) would react, but in the case of irreversible inhibition, this step is blocked because the enzyme is permanently modified.
Thus, Q irreversibly modifies the enzyme, halting the reaction cycle. This is characteristic of irreversible inhibitors acting through a ping-pong bisubstrate mechanism.
Summary
The COX2–Q complex features a covalent bond between the serine hydroxyl and a reactive group of Q, mimicking the inactivation caused by aspirin but with higher specificity. The mechanism of inhibition reflects a ping-pong type bisubstrate model, where Q acts as a substrate analog that irreversibly modifies the enzyme, preventing further catalytic action. This greater selectivity for COX2 over COX1 makes Q a potentially safer therapeutic option for reducing inflammation.
