title: Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging.
abstract: The cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase, are primary targets of organophosphates (OPs). Exposure to OPs can lead to serious cardiovascular complications, respiratory compromise, and death. Current therapy to combat OP poisoning involves an oxime reactivator (2-PAM, obidoxime, TMB4, or HI-6) combined with atropine and on occasion an anticonvulsant. Butyrylcholinesterase, administered in the plasma compartment as a bio-scavenger, has also shown efficacy but is limited by its strict stoichiometric scavenging, slow reactivation, and a propensity for aging. Here, we characterize 10 human (h) AChE mutants that, when coupled with an oxime, give rise to catalytic reactivation and aging resistance of the soman conjugate. With the most efficient human AChE mutant Y337A/F338A, we show enhanced reactivation rates for several OP-hAChE conjugates compared with wild-type hAChE when reactivated with HI-6 (1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4'-carbamoyl-1-pyridinium)). In addition, we interrogated an 840-member novel oxime library for reactivation of Y337A/F338A hAChE-OP conjugates to delineate the most efficient oxime-mutant enzyme pairs for catalytic bio-scavenging. Combining the increased accessibility of the Y337A mutation to oximes within the space-impacted active center gorge with the aging resistance of the F338A mutation provides increased substrate diversity in scavenging potential for aging-prone alkyl phosphate inhibitors.
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0650, USA.
authors: Rory
authors: R
authors: Cochran
authors: Jaroslaw
authors: J
authors: Kalisiak
authors: Tuba
authors: T
authors: Küçükkilinç
authors: Zoran
authors: Z
authors: Radic
authors: Edzna
authors: E
authors: Garcia
authors: Limin
authors: L
authors: Zhang
authors: Kwok-Yiu
authors: KY
authors: Ho
authors: Gabriel
authors: G
authors: Amitai
authors: Zrinka
authors: Z
authors: Kovarik
authors: Valery V
authors: VV
authors: Fokin
authors: K Barry
authors: KB
authors: Sharpless
authors: Palmer
authors: P
authors: Taylor
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000375:Aging; D020134:Catalytic Domain / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D010755:Organophosphates / Q000737:chemistry*; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; C022870:asoxime chloride