title: Stereospecific cholinesterase inhibition by O,S-diethylphenylphosphonothioate.
abstract: The inhibition kinetics and stereospecificity of the chiral nerve agent derivative O,S-diethylphenylphosphonothioate (DEPP) were examined for two forms of acetylcholinesterase (human and eel) and equine butyrylcholinesterase. Both S- and R-DEPP are poor inhibitors of eel AChE (IC50150μM), consistent with a large, nondiscriminatory binding interaction in the active site of this enzyme. However, S-DEPP is active against human and equine AChE with low μM IC50s. DEPP stereospecificities (S/R) toward these enzymes are moderate (20) relative to other cholinesterase-organophosphate (OP) systems. Pralidoxime, a common rescue agent, affects a modest recovery of both hAChE and eqBChE from treatment with S-DEPP. This result is consistent with expected chemical modification by DEPP and indicates that a measurable amount of the enzyme-phosphonate adduct does not undergo aging. Kinetic analysis of inhibition of both hAChE and eqBChE by S-DEPP yields KIvalues near 8μM and k2values of about 0.10min-1. In both cases, the reaction is practically irreversible. Second order rate constants calculated from these values are similar to those obtained previously using other thio-substituted OPs with bulky groups. Since BChE has a more accommodating acyl pocket than AChE, the similar behaviors of both enzymes toward S-DEPP is notable and is likely a reflection of the weakened potency of DEPP relative to chemical warfare agents.
authors.affiliation: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sneathen
authors.affiliation: Department of Chemistry, Lewis and Clark College, Portland, OR 97219, United States.
authors.forename: Sara Glazier
authors.initials: SG
authors.lastname: Frojen
authors.affiliation: Department of Chemistry, Lewis and Clark College, Portland, OR 97219, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Kuo
authors.affiliation: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States. Electronic address: cdup@umsl.edu.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Dupureur
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007700:Kinetics; D009946:Organothiophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase