Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging

Rory Cochran, Jarosław Kalisiak, Tuba Küçükkilinç, Zoran Radić, Edzna Garcia, Limin Zhang, Kwok Yiu Ho, Gabriel Amitai, Zrinka Kovarik, Valery V. Fokin, K. Barry Sharpless, Palmer Taylor

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

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 bioscavenging. 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 agingprone alkyl phosphate inhibitors.

Original languageEnglish
Pages (from-to)29718-29724
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number34
DOIs
Publication statusPublished - 26 Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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