Naslov
Interactions of butane, but-2-ene or xylene-like linked bispyridinium para-aldoximes with native and tabun-inhibited human cholinesterases

Autori
Čalić, Maja ; Kovarik, Zrinka ; Bosak, Anita

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
The IXth International Meeting on Cholinesterases, Suzhou, Kina, Program Book / - , 2007

Skup
The IXth International Meeting on Cholinesterses

Mjesto i datum
Suzhou, Kina, 06.05.2007. - 10.05.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
acetylcholinesterase; tabun; inhibition; aldoxime; reactivation

Sažetak
Kinetic parameters were evaluated for inhibition of native and reactivation of tabun-inhibited human erythrocyte acetylcholinesterase (AChE ; EC 3.1.1.7) and human plasma butyrylcholinesterase (BChE ; EC 3.1.1.8) by three bispyridinium para-aldoximes differing only in the type of the linker: K074 [1, 1'-(butane-1, 4-diyl)bis(4-(hydroxyl-iminomethyl)pyridinium) bromide], K075 [1, 1'-(but-2-ene-1, 4-diyl)bis(4-(hydroxyliminomethyl)pyridinium) bromide], K114 [1, 1'-(1, 4-phenylenebis(methylene))bis(4-(hydroxyliminomethyl)pyridinium) bromide]. All tested aldoximes reversibly inhibited both cholinesterases with the preference for binding to the native AChE. The enzyme-aldoxime dissociation constants, Ki, ranged from 0.010 mM to 0.030 mM for AChE and from 0.050 mM to 0.30 mM for BChE. The catalytic site of both cholinesterases showed the highest affinity for K114, containing xylene-like linker, while the affinity for K074 was similar to the affinity for K075. The reactivation of tabun-inhibited AChE was efficient only by K074 and K075. Their overall reactivation rate constants were around 1700 min-1M-1, that is, five times higher than for the classical bispyridinium para-aldoxime TMB-4. The reactivation of tabun-inhibited AChE assisted by K114 was slow and reached 90% after 20 h. Since the aldoxime binding affinity of tabun-inhibited AChE was similar for all tested aldoximes (and corresponded to their Ki), the rate of the nucleophilic displacement of the phosphoryl-moiety from the active site serine was the limiting factor for AChE reactivation. On the other hand, none of the aldoximes displayed a significant reactivation of tabun-inhibited BChE. Even after 20 h, the reactivation maximum was 60% for 1 mM K074 and K075, and only 20% for 1 mM K114. However, lower BChE affinities for K074 and K075 compared to AChE suggest that the fast tabun-inhibited AChE reactivation by these compounds would not be obstructed by their interactions with BChE in vivo.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

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