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
  • 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.