Naslov
Efficient oxime reactivation of cholinesterases enables the catalytic turnover of organophosphorus compounds

Autori
Kovarik, Zrinka ; Katalinić, Maja ; Maček, Nikolina ; Radić, Zoran ; Taylor, Palmer

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

Izvornik
The FEBS Journal, Vol. 280, Supplement 1 / - Oxford : Wiley-Blackwell, 2013, 166-166

Skup
The 38th FEBS Congress: "Mechanisms in Biology"

Mjesto i datum
Sankt Peterburg, Ruska Federacija, 06.07.2013. - 11.07.2013

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
bioscavenger ; butyrylcholinesterase ; soman ; tabun

Sažetak
The high toxicity of organophosphorus compounds arises from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings which lead to life-threatening toxic manifestations call for immediate treatment, which usually consists of a combined administration of anticholinergic drugs and an oxime as the reactivator of AChE. A new approach to reduce the in vivo toxicity of organophosphorus compounds includes the use of bioscavengers – enzymes that could react with the nerve agent before it inhibits acetylcholinesterase. Butyrylcholinesterase (BChE), naturally present in plasma, the liver, the small intestine, smooth muscles, heart, adipose tissue, and the brain, is considered an endogenous bioscavenger of anticholinesterase compounds. Due to the limited concentration of BChE in the organism, a stochiometric reduction of nerve agents is not sufficient. Others have shown that injections of milligram quantities of purified human BChE can be efficient for stoichiometric scavenging, but are prohibitively expensive for treatment of wider populations. In addition, this stochiometric approach has limitations mostly due to the inability of currently applied reactivators to reactivate tissue AChE efficiently, particularly when it is repeatedly phosphorylated by an excess of tabun or soman remaining in circulation upon exposure. Our recent studies have shown that AChE mutagenesis enables oximes to substantially accelerate the reactivation of the soman-enzyme conjugate which resists aging. We created a human AChE mutant, Y337A/F338A, to combine the increased accessibility of conjugated phosphorus to oximes provided by the Y337A mutation with the aging resistance of the F338A mutation. We also designed a library of new oximes where we identified efficient reactivators of the Y337A human AChE inhibited by tabun that accelerate the reactivation rate 10-times in comparison to the AChE w.t. Our overall findings indicate that distinct human AChE mutants have a catalytic bioscavenging potential when combined with oximes, which has been proven effective in soman or tabun in vitro exposure.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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