title: β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine.
abstract: 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.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ponzano
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mengatto
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Dionisi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Karacsonyi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bertozzi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Garau
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Glauco
authors.initials: G
authors.lastname: Tarozzo
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Reggiani
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza del Rinascimento 6, I-61029 Urbino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.affiliation: Pharmaceutical Department, University of Parma , 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy ; Departments of Pharmacology, University of California, Irvine , 360 MSRII, California 92697-4625, United States.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
keywords: NAAA; covalent inhibitors; cysteine amidase; high resolution mass spectrometry; proteomics