Investigation of the inhibition mechanism of coumarins on chymotrypsin by mass spectrometry

✍ Scribed by Lionel Pochet; Marc Dieu; Raphaël Frédérick; Ann-Marie Murray; Isabelle Kempen; Bernard Pirotte; Bernard Masereel

• Book ID: 104205350
• Publisher: Elsevier Science
• Year: 2003
• Tongue: French
• Weight: 226 KB
• Volume: 59
• Category: Article
• ISSN: 0040-4020
• DOI: 10.1016/s0040-4020(03)00660-4

✦ Synopsis

6-Chloromethylcoumarin derivatives are known to express a marked inhibitory potency against serine proteases. However, their mechanism of inhibition remains unclear. In order to confirm the postulated mechanism, we use mass spectrometry. The shift mass obtained after inactivation by two compounds, which differ only by the nature of the leaving group (chloride or acetate) was in agreement with an alkylenzyme formation. With another compound devoid of a latent alkylating group, the shift mass obtained with the complex corresponds to an acylenzyme resulting from the interaction of the serine residue with the lactone carbonyl group. These results clearly demonstrate that the inhibition is not due to an attack of the exocyclic carbonyl group by the active serine but rather result from a nucleophilic attack on the intracyclic carbonyl group.