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Disulfiram is an Inhibitor of Human Purified Monoacylglycerol Lipase, the Enzyme Regulating 2‐Arachidonoylglycerol Signaling
Author(s) -
Labar Geoffray,
Bauvois Cédric,
Muccioli Giulio G.,
Wouters Johan,
Lambert Didier M.
Publication year - 2007
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700139
Subject(s) - monoacylglycerol lipase , endocannabinoid system , disulfiram , 2 arachidonoylglycerol , enzyme , chemistry , biochemistry , serine hydrolase , pharmacology , cannabinoid receptor , biology , receptor , serine , antagonist
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the termination of endocannabinoid signaling. Its crucial role in 2‐arachidonoylglycerol (2‐AG) metabolism, together with the numerous pharmacological properties mediated by this endocannabinoid, emphasize the interest in MAGL as therapeutic target, along with the need to design potent and selective inhibitors. Meanwhile, the complexity of 2‐AG degradation pathways underscores the need to use a purified source of enzyme in evaluation studies of new inhibitors. We report here the first heterologous expression and purification of human MAGL. A highly pure protein was obtained and allowed us to measure the affinity of several MAGL inhibitors for the human enzyme. Importantly, disulfiram (tetraethylthiuram disulfide), a compound used to treat alcoholism, and other disulfide‐containing compounds were shown to inhibit MAGL with good potency, likely through an interaction with cysteine residues.