2. Academic Validation
  3. β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

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

  • ACS Med Chem Lett. 2012 Apr 6;3(5):422-6. doi: 10.1021/ml300056y.
Andrea Armirotti 1,  Elisa Romeo 1,  Stefano Ponzano 1,  Luisa Mengatto 1,  Mauro Dionisi 1,  Claudia Karacsonyi 1,  Fabio Bertozzi 1,  Gianpiero Garau 1,  Glauco Tarozzo 1,  Angelo Reggiani 1,  Tiziano Bandiera 1,  Giorgio Tarzia 2,  Marco Mor 3,  Daniele Piomelli 4
Affiliations

Affiliations

  • 1 Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
  • 2 Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo" , Piazza del Rinascimento 6, I-61029 Urbino, Italy.
  • 3 Pharmaceutical Department, University of Parma , 43124 Parma, Italy.
  • 4 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.
PMID: 24900487 DOI: 10.1021/ml300056y
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.

Keywords

NAAA; covalent inhibitors; cysteine amidase; high resolution mass spectrometry; proteomics.

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