Naslov
Enhancement in pyridinium oxime-assisted reactivation of tabun-inhibited acetylcholinesterase achieved by active site mutations

Autori
Kovarik, Zrinka ; Katalinić, Maja ; Maček Hrvat, Nikolina ; Šinko, Goran ; Zorbaz, Tamara ; Bosak, Anita

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

Izvornik
Programme and Abstract Book, Military Medical Science Letters - Special Issue on the occasion of the 13th International Meeting on Cholinesterases and the 7th International Conference on Paraoxonases, Hradec Králové, Republika Češka, 2018 / Korábečný, Jan ; Soukup, Ondrej - Hradec Kralove : University of Defence, Faculty of Military Health Sciences, Czech Republic, 2018, 35-35

Skup
13th International Meeting on Cholinesterases ; 7th International Conference on Paraoxonases

Mjesto i datum
Hradec Králové, Češka Republika, 09.09.2018. - 14.09.2018

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
nerve agents ; antidotes ; 2-PAM ; HI-6

Sažetak
Tabun represents a phosphoramide class of organophosphosphates that are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme in neurotransmission. The currently used therapy in excessive cholinergic stimulation consists of the muscarinic antagonist of acetylcholine stimulation, an anti-seizure drug when indicated and an oxime as the reactivator of inhibited AChE. Since common oximes are particularly ineffective in tabun exposure, we probed the reactivation of phosphoramidate conjugates in more depth by using mutants of AChE and pyridinium oximes to reveal the structural subtleties and yield more information on the architecture of the active centre gorge needed for the reactivation of phosphoramidate agents used in terrorism and as pesticides. Our results indicated that the replacement of aromatic residues with aliphatic ones at the acyl pocket and choline binding site mostly interfered with the stabilization of the oxime’s pyridinium ring(s) in the proper orientation of the oxime group toward the phosphorylated active site serine. The peripheral binding site mutation resulted in a 2-5 fold increase in the reactivation rates by bis-pyridinium oximes when compared to the AChE wild type. In the case of mono-pyridinium oximes, we reported a 150-fold enhancement of the maximal reactivation rate for the choline binding site mutation, while the molecular recognition seemed to remain preserved. Therefore, our results emphasized the positive effect of several mutations on oxime embedding and orientation into a position for productive interactions with the tabun-phosphorylated active site serine indicating a future potential for further development of pseudo-catalytic bioscavengers based on AChE mutants. Acknowledgment: This work was supported by the Croatian Science Foundation (no. 4307). Key words: nerve agents, antidotes, 2-PAM, HI-6

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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