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

被引：31

作者：

Armirotti, Andrea ^{[1
]}

Romeo, Elisa ^{[1
]}

Ponzano, Stefano ^{[1
]}

Mengatto, Luisa ^{[1
]}

Dionisi, Mauro ^{[1
]}

Karacsonyi, Claudia ^{[1
]}

Bertozzi, Fabio ^{[1
]}

Garau, Gianpiero ^{[1
]}

Tarozzo, Glauco ^{[1
]}

Reggiani, Angelo ^{[1
]}

Bandiera, Tiziano ^{[1
]}

Tarzia, Giorgio ^{[4
]}

Mor, Marco ^{[3
]}

Piomelli, Daniele ^{[1
,2
]}

机构：

[1] Ist Italian Tecnol, Dept Drug Discovery & Dev, I-16132 Genoa, Italy

[2] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA

[3] Univ Parma, Dept Pharmaceut, I-43124 Parma, Italy

[4] Univ Urbino Carlo Bo, Dipartimento Sci Biomol, I-61029 Urbino, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 05期

关键词：

NAAA; cysteine amidase; covalent inhibitors; high resolution mass spectrometry; proteomics; ANTIDEPRESSANT-LIKE ACTIVITY; ENDOCANNABINOID MECHANISM; ANANDAMIDE HYDROLYSIS; CANNABINOID RECEPTOR; PAIN INITIATION; HYDROLASE; URB597; PALMITOYLETHANOLAMIDE; BIOSYNTHESIS; MODULATION;

D O I：

10.1021/ml300056y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 beta-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.

引用

页码：422 / 426

页数：5

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