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Use of V agents and V-analogue compounds to probe the active site of atypical butyrylcholinesterase from Oryzias latipes.

Abstract：

:The atypical butyrylcholinesterase (aBuChE) from Oryzias latipes shares approximately 65% sequence similarity to both acetylcholinesterase and butyrylcholinesterase and was studied for its capacity to spontaneously reactivate following inhibition by organophosphorus nerve agents. Like other cholinesterases, aBuChE was inhibited by all G- and V-type nerve agents. Interestingly, aBuChE was able to undergo spontaneous reactivation after inhibition with VR (t1/2 = 5.5 ± 0.2 h). Mass spectrometry of aBuChE after VR inhibition confirmed the presence of a covalently bound adduct of the size expected for non-aged VR on the peptide containing the active site serine. To understand the effect of substrate volume on rates of reactivation, the capacity of aBuChE to bind and spontaneously reactivate after inhibition with five V-agent analogues was examined. No appreciable reactivation was detected for enzyme inhibited by V2 (VX with O-isopropyl on retained group), V4 (VX with N-diethyl leaving group termination), or V5 (VX with N-dimethyl leaving group termination). Minimal reactivation was detected with V1 (VX with O-propyl on retained group). Conversely, spontaneous reactivation was observed when aBuChE was inhibited by V3 (VX with O-isobutyl on retained group; t1/2 = 6.3 ± 0.4 h). The data suggest that the ability of aBuChE to spontaneously reactivate after inhibition by V-agent analogues is related to the structure of the retained group. These results provide structural information that may shed light on the design of improved small molecule reactivators of nerve agent-inhibited acetylcholinesterase or butyrylcholinesterase, and further suggest that re-engineering the active site of a cholinesterase could result in enzymes with clinically relevant rates of nerve agent hydrolysis.

journal_name

Chem Biol Interact

journal_title

Chemico-biological interactions

authors

Kirkpatrick MG,diTargiani RC,Sweeney RE,Otto TC

doi

10.1016/j.cbi.2016.03.016

subject

Has Abstract

pub_date

2016-11-25 00:00:00

pages

182-186

issue

Pt B

eissn

0009-2797

issn

1872-7786

pii

S0009-2797(16)30086-2

journal_volume

259

pub_type

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Use of V agents and V-analogue compounds to probe the active site of atypical butyrylcholinesterase from Oryzias latipes.