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β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

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journal contribution
posted on 10.05.2012, 00:00 by Andrea Armirotti, Elisa Romeo, Stefano Ponzano, Luisa Mengatto, Mauro Dionisi, Claudia Karacsonyi, Fabio Bertozzi, Gianpiero Garau, Glauco Tarozzo, Angelo Reggiani, Tiziano Bandiera, Giorgio Tarzia, Marco Mor, Daniele Piomelli
The cysteine amidase N-acylethanolamine acid amidase (NAAA) is a member of the N-terminal nucleophile class of enzymes and a potential target for anti-inflammatory drugs. We investigated the mechanism of inhibition of human NAAA by substituted β-lactones. We characterized pharmacologically a representative member of this class, ARN077, and showed, using high-resolution liquid chromatography–tandem mass spectrometry, that this compound forms a thioester bond with the N-terminal catalytic cysteine in human NAAA.