Novel Human Butyrylcholinesterase Variants: Toward Organophosphonate Detoxication | Zendy

Mary A. Dwyer | Zendy; Sacha Javor | Zendy; Daniel A. J. Ryan | Zendy; Emily M. Smith | Zendy; Beilin Wang | Zendy; Jun Zhang | Zendy; John R. Cashman | Zendy

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Novel Human Butyrylcholinesterase Variants: Toward Organophosphonate Detoxication

Author(s) -

Mary A. Dwyer,

Sacha Javor,

Daniel A. J. Ryan,

Emily M. Smith,

Beilin Wang,

Jun Zhang,

John R. Cashman

Publication year - 2014

Publication title -

biochemistry

Language(s) - Uncategorized

Resource type - Journals

SCImago Journal Rank - 1.43

H-Index - 253

eISSN - 1520-4995

pISSN - 0006-2960

DOI - 10.1021/bi500491w

Subject(s) - nerve agent , sarin , soman , butyrylcholinesterase , chemistry , detoxication , combinatorial chemistry , esterase , rational design , enzyme , biochemistry , acetylcholinesterase , biology , genetics , aché

Human butyrylcholinesterase (hBChE) is currently being developed as a detoxication enzyme for stoichiometric binding and/or catalytic hydrolysis of organophosphates. Herein, we describe the use of a molecular evolution method to develop novel hBChE variants with increased resistance to stereochemically defined nerve agent model compounds of soman, sarin, and cyclosarin. Novel hBChE variants (Y332S, D340H, and Y332S/D340H) were identified with an increased resistance to nerve agent model compounds that retained robust intrinsic catalytic efficiency. Molecular dynamics simulations of these variants revealed insights into the mechanism by which these structural changes conferred nerve agent model compound resistance.

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