Why is Aged Acetylcholinesterase So Difficult to Reactivate?
AbstractOrganophosphorus agents are potent inhibitors of acetylcholinesterase. Inhibition involves successive chemical events. The first is phosphylation of the active site serine to produce a neutral adduct, which is a close structural analog of the acylation transition state. This adduct is unreactive toward spontaneous hydrolysis, but in many cases can be reactivated by nucleophilic medicinal agents, such as oximes. However, the initial phosphylation reaction may be followed by a dealkylation reaction of the incipient adduct. This reaction is called aging and produces an anionic phosphyl adduct with acetylcholinesterase that is refractory to reactivation. This review considers why the anionic aged adduct is unreactive toward nucleophiles. An alternate approach is to realkylate the aged adduct, which would render the adduct reactivatable with oxime nucleophiles. However, this approach confronts a considerable—and perhaps intractable—challenge: the aged adduct is a close analog of the deacylation transition state. Consequently, the evolutionary mechanisms that have led to transition state stabilization in acetylcholinesterase catalysis are discussed herein, as are the challenges that they present to reactivation of aged acetylcholinesterase. View Full-Text
Scifeed alert for new publicationsNever miss any articles matching your research from any publisher
- Get alerts for new papers matching your research
- Find out the new papers from selected authors
- Updated daily for 49'000+ journals and 6000+ publishers
- Define your Scifeed now
Quinn, D.M.; Topczewski, J.; Yasapala, N.; Lodge, A. Why is Aged Acetylcholinesterase So Difficult to Reactivate? Molecules 2017, 22, 1464.
Quinn DM, Topczewski J, Yasapala N, Lodge A. Why is Aged Acetylcholinesterase So Difficult to Reactivate? Molecules. 2017; 22(9):1464.Chicago/Turabian Style
Quinn, Daniel M.; Topczewski, Joseph; Yasapala, Nilanthi; Lodge, Alexander. 2017. "Why is Aged Acetylcholinesterase So Difficult to Reactivate?" Molecules 22, no. 9: 1464.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.