title: Novel human butyrylcholinesterase variants: toward organophosphonate detoxication.
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.
authors.affiliation: Human BioMolecular Research Institute , 5310 Eastgate Mall, San Diego, California 92121, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Dwyer
authors.forename: Sacha
authors.initials: S
authors.lastname: Javor
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ryan
authors.forename: Emily M
authors.initials: EM
authors.lastname: Smith
authors.forename: Beilin
authors.initials: B
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
mesh_terms: D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000235:genetics; D002092:Butyrylthiocholine / Q000737:chemistry; D002619:Chemical Warfare Agents / Q000737:chemistry* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D019020:Directed Molecular Evolution; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000633:toxicity; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012524:Sarin / Q000737:chemistry* / Q000633:toxicity; D012999:Soman / Q000737:chemistry* / Q000633:toxicity
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D002092:Butyrylthiocholine; D012999:Soman; D012524:Sarin; D002091:Butyrylcholinesterase; C053914:cyclohexyl methylphosphonofluoridate