S-acylation of cysteine by O-acetylsalicylic anhydride: a possible mechanism for aspirin hypersensitivity?

In order to elucidate the possible reaction pathways for the acylation of protein by O-acetylsalicylic anhydride, the mechanism of the reaction between L-cysteine and O-acetylsalicylic anhydride was studied. O-Acetylsalicylic anhydride reacts with L-cysteine via a consecutive kinetic pathway. The thiol anion first reacts with the anhydride to form an intermediate thiol ester which then undergoes an intramolecular rearrangement to form the stable N-(O-acetylsalicyloyl)-2-amino-3-thiopropionic acid, 5. The importance of the free amino group in the intramolecular reaction was established by the observed stability of the S-(O-acetylsalicyloyl) derivative of N-acetylcysteine under similar reaction conditions. The formation of the thiol ester was pH dependent, suggesting that the thiol anion was the attacking species. The acyl transfer to the adjacent amino group was catalyzed by both phosphate and acetate buffers. The results suggest that the reaction of O-acetylsalicylic anhydride with the thiol-containing amino acids of a protein molecule may proceed via formation of an initial thio ester, followed by an S to N intramolecular acyl transfer to form an immunogenic amide.