title: A step toward the reactivation of aged cholinesterases--crystal structure of ligands binding to aged human butyrylcholinesterase.
abstract: Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase.
authors.affiliation: Département de Toxicologie, Institut de Recherche Biomédicale des Armées - CRSSA, La Tronche, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Wandhammer
authors.forename: Martijn
authors.initials: M
authors.lastname: de Koning
authors.forename: Marco
authors.initials: M
authors.lastname: van Grol
authors.forename: Mélanie
authors.initials: M
authors.lastname: Loiodice
authors.forename: Laura
authors.initials: L
authors.lastname: Saurel
authors.forename: Daan
authors.initials: D
authors.lastname: Noort
authors.forename: Maurice
authors.initials: M
authors.lastname: Goeldner
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
mesh_terms: D000478:Alkylation; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D010766:Phosphorylation; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D012999:Soman / Q000633:toxicity
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D008024:Ligands; D011220:Pralidoxime Compounds; D011994:Recombinant Proteins; D012694:Serine; D012999:Soman; D002091:Butyrylcholinesterase; C028797:pralidoxime