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Published on: December 20, 2017
Novel human butyrylcholinesterase variants: toward organophosphonate detoxication
Mary Dwyer1, Sacha Javor, Daniel A Ryan
1Human BioMolecular Research Institute , 5310 Eastgate Mall, San Diego, California 92121, United States.
Abstract:
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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