Observation of an Arsenic Adduct in an Acetyl Esterase Crystal Structure

• Published in: The Journal of biological chemistry 2003-01, Vol.278 (3), p.2008-2014
• Main Authors: Zhu, Xueyong, Larsen, Nicholas A., Basran, Amrik, Bruce, Neil C., Wilson, Ian A.
• Format: Article
• Language: English
• Subjects: Acetylesterase - chemistry; Acetylesterase - genetics; Arsenic - chemistry; Binding Sites; Cell Line, Transformed; Cloning, Molecular; Crystallography, X-Ray; Models, Molecular; Protein Conformation; Substrate Specificity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210103200

The crystal structures of an acetyl esterase, HerE, and its complex with an inhibitor dimethylarsinic acid have been determined at 1.30- and 1.45-Å resolution, respectively. Although the natural substrate for the enzyme is unknown, HerE hydrolyzes the acetyl groups from heroin to yield morphine and from phenyl acetate to yield phenol. Recently, the activity of the enzyme toward heroin has been exploited to develop a heroin biosensor, which affords higher sensitivity than other currently available detection methods. The crystal structure reveals a single domain with the canonical α/β hydrolase fold with an acyl binding pocket that snugly accommodates the acetyl substituent of the substrate and three backbone amides that form a tripartite oxyanion hole. In addition, a covalent adduct was observed between the active site serine and dimethylarsinic acid, which inhibits the enzyme. This crystal structure provides the first example of an As-containing compound in a serine esterase active site and the first example of covalent modification of serine by arsenic. Thus, the HerE complex reveals the structural basis for the broad scope inhibition of serine hydrolases by As(V)-containing organic compounds.