engleski

Oxime-assisted reactivation of phosphorylated acetylcholinesterase and butyrylcholinesterase

Phosphorylation of serine in the active site of acetylcholinesterase (AChE) and of butyrylcholinesterase (BChE) inactivates both enzymes. AChE is essential enzyme in neurotransmission, while BChE is an endogenous stoichiometric bioscavenger of organophosphorus compounds (OP), including insecticides and nerve agents. Oximes are reactivators of both phosphorylated cholinesterases, but none of the newly synthesised or currently used oximes like 2-PAM, HI-6, TMB-4, and obidoxime, have shown satisfactory reactivation potency in tabun poisoning. This is especially true for reactivation of tabun-inhibited BChE. Reactivation efficiency is primarily attributed to the nucleophilic displacement rate of organophosphate, but varies with the structure of the oxime. Inthis study we tested reactivation of tabun-inhibited AChE and BChE with bispyridinium oximes varying in the length and type of the linker between rings, and in the position of the oxime group on the ring. Tabun-inhibited AChE was completely reactivated by K203 [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide] with the overall reactivation rate constants of 1806 L mol1 min1, which singes out this oxime as a very potent reactivator of tabun-inhibited AChE. Among the tested oximes, the most potent reactivators of tabun inhibited BChE were K117 [1, 1'-(2, 2'-oxybis(ethane-2, 1-diyl))bis(4-hydroxyiminomethyl pyridinium) bromide] and K127 [4-carbamoyl-1-(2-(2-(4-(hydroxyiminomethyl) pyridinium-1-yl)ethoxy)ethyl)pyridinium bromide]. The maximum reactivation of BChE of 70 % was obtained in 50 min, which is the shortest time so far according to literature and our previous data. This is no surprise, since all selected oximes were designed as reactivators of phosphorylated AChE. Our findings may provide a platform for further modifications and development of more potent antidotes in OP poisoning.

Antidote ; Bioscavenger ; Cholinesterase ; Nerve agents ; Reactivation ; Tabun

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