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Review
. 2017 Sep 4;22(9):1464.
doi: 10.3390/molecules22091464.

Why is Aged Acetylcholinesterase So Difficult to Reactivate?

Daniel M Quinn  1 , Joseph Topczewski  2 , Nilanthi Yasapala  3 , Alexander Lodge  4
Affiliations
Review

Why is Aged Acetylcholinesterase So Difficult to Reactivate?

Daniel M Quinn et al. Molecules. .

Abstract

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.

Keywords: acetylcholinesterase; aging; inhibition; organophosphorus agent; reactivation; transition state.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Inhibition of AChE by the organophosphorus nerve agent sarin.
Figure 2
Figure 2
Thermodynamic cycle for estimation of transition state stabilization in AChE catalysis. E, EA, A, P, TSu, and TSE are respectively free enzyme, Michaelis complex, substrate, product, transition state of the spontaneous hydrolysis reaction, and transition state of the AChE-catalyzed reaction. Km and kcat are the respective Michaelis constant and turnover number of the AChE-catalyzed reaction; ku and KTS are respectively the rate constant of the spontaneous hydrolysis reaction and the dissociation constant of the enzymic transition state.
Figure 3
Figure 3
Substituted 2-Methoxy-1-methylpyridiniums as phosphonate anion methylating agents. Reactions were run in DMSO-d6 at 25 °C and were monitored by 1H-NMR spectroscopy [24].
See this image and copyright information in PMC

References

    1. Dingeman J., Jupa R. Chemical warfare in the Iran-Iraq conflict. Strategy Tactics. 1987;113:51–52.
    1. Tu A.T. Overview of sarin terrorist attacks in Japan. ACS Symp. Ser. 2000;745:304–317.
    1. Dolgin E. Syrian gas attack reinforces need for better anti-sarin drugs. Nat. Med. 2013;19:1194–1195. doi: 10.1038/nm1013-1194. - DOI - PubMed
    1. Paddock R.C., Sang-Hun C. Kim Jong-nam was killed by VX nerve agent, Malaysians say. New York Times. Feb 23, 2017.
    1. Malany S., Sawai M., Sikorski R.S., Seravalli J., Quinn D.M., Radić Z., Taylor P., Kronman C., Velan B., Shafferman A. Transition state structure and rate determination for the acylation stage of acetylcholinesterase catalyzed hydrolysis of (acetylthio)choline. J. Am. Chem. Soc. 2000;122:2981–2987. doi: 10.1021/ja9933590. - DOI

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