Details

Autor(en) / Beteiligte

• Cebrián-Prats, Anna
• González-Lafont, Àngels
• Lluch, José M

Titel

Understanding the Molecular Details of the Mechanism That Governs the Oxidation of Arachidonic Acid Catalyzed by Aspirin-Acetylated Cyclooxygenase‑2

Ist Teil von

• ACS catalysis, 2020-01, Vol.10 (1), p.138-153

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandin G2 (PGG2) from arachidonic acid (AA). Its activity is substantially altered by aspirin, a nonsteroidal antiinflammatory drug that irreversibly inhibits COX-2 by acetylation of its Ser530 residue. So far, it has been widely accepted that in the aspirin-acetylated COX-2, PGG2 synthesis is blocked, whereas the acetylated enzyme still catalyzes the formation of hydroxy­eicosatetraenoic acid 15R-HETE as the main product. However, recent experiments detected residual COX activity in recombinant human acetylated COX-2 with formation of prostaglandins, a surprising result that could not be rationalized. In fact, a complete molecular understanding of aspirin action is still lacking, and contradictory explanations have been given for the formation of the highly controlled stereochemical products. We have combined here molecular dynamics simulations and quantum mechanics/molecular mechanics calculations to study each step of the aspirin-inhibited catalytic mechanism. Our results confirm that 15R-HPETE (then reduced to 15R-HETE) is the main product of the AA oxidation catalyzed by aspirin-acetylated COX-2, being clearly more favorable than the formation of 15S-HPETE. The 15R-HPETE synthesis is kinetically dominant and inhibits the formation of the (9R, 11R) bicyclo endoperoxides to give PGH2, which can still be obtained as a minor product, as detected experimentally. Instead, the synthesis of isoprostanes does not happen because it is not kinetically competitive at all with the formation of 15R-HETE.