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Why is Aged Acetylcholinesterase So Difficult to Reactivate?

Organophosphorus 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 tow...

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Autores principales: Quinn, Daniel M., Topczewski, Joseph, Yasapala, Nilanthi, Lodge, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151809/
https://www.ncbi.nlm.nih.gov/pubmed/28869561
http://dx.doi.org/10.3390/molecules22091464
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author Quinn, Daniel M.
Topczewski, Joseph
Yasapala, Nilanthi
Lodge, Alexander
author_facet Quinn, Daniel M.
Topczewski, Joseph
Yasapala, Nilanthi
Lodge, Alexander
author_sort Quinn, Daniel M.
collection PubMed
description Organophosphorus 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.
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spelling pubmed-61518092018-11-13 Why is Aged Acetylcholinesterase So Difficult to Reactivate? Quinn, Daniel M. Topczewski, Joseph Yasapala, Nilanthi Lodge, Alexander Molecules Review Organophosphorus 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. MDPI 2017-09-04 /pmc/articles/PMC6151809/ /pubmed/28869561 http://dx.doi.org/10.3390/molecules22091464 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Quinn, Daniel M.
Topczewski, Joseph
Yasapala, Nilanthi
Lodge, Alexander
Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title_full Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title_fullStr Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title_full_unstemmed Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title_short Why is Aged Acetylcholinesterase So Difficult to Reactivate?
title_sort why is aged acetylcholinesterase so difficult to reactivate?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151809/
https://www.ncbi.nlm.nih.gov/pubmed/28869561
http://dx.doi.org/10.3390/molecules22091464
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