Naslov
Oxime-assisted acetylcholinesterase catalytic scavengers of organophosphates that resist aging

Autori
Cochran, Rory ; Kalisiak, Jarosław ; Kucukkilinc, Tuba ; Radić, Zoran ; Garcia, Edzna ; Zhang , Limin ; Ho, Kwok-Yiu ; Amitai, Gabriel ; Kovarik, Zrinka ; Fokin, Valery V. ; Sharpless, K. Barry ; Taylor, Palmer

Izvornik
The Journal of Biological Chemistry (0021-9258) 286 (2011), 34; 29718-29724

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
acetylcholinesterase ; molecular modeling ; molecular pharmacology ; site directed mutagenesis ; toxicology ; AChE reactivation ; oxime reactivation ; aging resistance ; catalytic bio-scavenger ; organophosphate intoxication

Sažetak
The cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are the primary targets of organophosphates (OPs). Exposure to OPs can lead to serious cardiovascular complications, respiratory compromise, and death. Current therapy to combat OP poisoning involves administration of an oxime reactivator (2-PAM, obidoxime, TMB4 or HI-6) combined with atropine and on occasion an anticonvulsant. BChE, administered in the plasma compartment as a bio-scavenger, has also shown efficacy, but is limited by its strict stoichiometric scavenging, slow reactivation, and a propensity for aging. Here we characterize ten human AChE mutants that, when coupled with an oxime, give rise to catalytic reactivation and aging resistance of the soman conjugate. With the most efficient human AChE mutant Y337A/F338A, we show enhanced reactivation rates for several OP-hAChE conjugates compared to wild-type hAChE when reactivated with HI-6. In addition, we interrogated a 840 member novel oxime library for reactivation of Y337A/F338A hAChE-OP conjugates to delineate the most efficient oxime-mutant enzyme pairs for catalytic bio-scavenging.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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