Naslov
Oxime-assisted reactivation of tabun-phosphorylated acetylcholinesterase mutants mutants
(Oxime-assisted reactivation of tabun-phosphorylated acetylcholinesterase mutants)

Autori
Kovarik, Zrinka ; Čalić, Maja

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

Izvornik
The FEBS Journal, Vol. 274, Supplement 1. 32nd FEBS Congress: "Molecular Machines" / - Oxford : Wiley-Blackwell, 2007, 234-234

Skup
32nd FEBS Congress, Molecular machines

Mjesto i datum
Beč, Austrija, 07.07.2007. - 12.07.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
acetylcholinesterase; mutants; reactivation; oximes; tabun; K048; K033

Sažetak
In the cholinergic system, acetylcholinesterase (AChE) is the primary target of nerve agent tabun. We investigated the reactivation of tabun-inhibited AChE and its site-directed mutants assisted by two bispyridinium oximes, K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] and K033 [1, 4-bis(2-hydroxyiminomethylpyridinium) butane dibromide]. AChE was modified within the acyl (Phe295Leu) and choline (Tyr337Ala) binding site of the active site gorge by replacing the aromatic amino acid residues with the aliphatic ones. K048, having para-positioned oxime group on the pyridinium ring, showed a high potency for the reactivation of tabun-inhibited w.t. AChE, because relatively low concentrations of oxime were able to completely reactivate AChE within 30– 60 min. On the other hand, reactivation of tabun-inhibited w.t. AChE by K033, having ortho-positioned oxime group on the pyridinium ring, was slow reaching only 50% after 24 h. Introduced mutations, Phe295Leu and Tyr337Ala, significantly lowered the reactivation efficacy of K048 but slightly enhanced the potency of K033 to reactivate tabun-inhibited AChE. The reason may be that the replacement of aromatic residues at the acyl and choline binding site interfered with the stabilization of the oxime’ s pyridinium ring(s) within the active site gorge in order to obtain the proper orientation of the oxime group forward to the phosphorylated active site serine. Although site-directed mutants of AChE are a powerful tool for investigating the role of some residues in reactivation, mutant that displays significant improvement in reactivation compared to the w.t. enzyme could be used as a pseudo catalytic scavenger of tabun in detoxification or decontamination.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA