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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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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. |
format | Online Article Text |
id | pubmed-6151809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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