Original scientific paper

https://doi.org/10.5562/cca1815

Reactivation of Tabun-inhibited Acetylcholinesterase Investigated by Two Oximes and Mutagenesis

Maja Katalinić orcid.org/0000-0001-7043-4291 ; Institute for Medical Research and Occupational Health, P.P. 291, HR-10001 Zagreb, Croatia
Zrinka Kovarik orcid.org/0000-0001-9863-886X ; Institute for Medical Research and Occupational Health, P.P. 291, HR-10001 Zagreb, Croatia

Abstract

The reactivation of tabun-inhibited AChE site-directed mutants assisted by two bispyridinium oximes, K048 (N-[4-(4-hydroxyiminomethylpyridinio)butyl]-4-carbamoylpyridinium dibromide) and K033 ((N,N' -butano)bis(2-hydroxyiminomethylpyridinium bromide) was studied to analyse the constraints on oxime-assisted reactivation. AChE was modified within the acyl (F295L, F297I) and choline (Y337A) binding site of the active site gorge. Results show that introduced mutations affected both the affinity of phosphorylated enzyme for oximes and the rate of nucleophilic displacement of phosphoryl moiety from the catalytic serine. Mutations significantly lowered the overall reactivation efficacy of K048, but slightly enhanced the potency of K033 to reactivate tabun-inhibited AChE. It seems that the replacement of aromatic residues with the aliphatic ones at the acyl and choline binding site greatly interfered with the stabilization of the oxime's pyridinium ring(s) within the active site gorge needed to obtain the proper orientation of the oxime group toward the phosphorylated active site serine. (doi: 10.5562/cca1815)

Keywords

acetylcholinesterase; butyrylcholinesterase; nerve agents; oxime; protection; reactivation

Hrčak ID:

81254

URI

https://hrcak.srce.hr/81254

Publication date:

11.5.2012.

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