The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M−1 min−1) and III (kr = 213 M−1 min−1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from Nε of His438 to Oγ of Ser203 for achieving successful reactivation.
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Cr(VI)-induced mitophagy contributes to mitochondrial loss, energy metabolism disorder, and cell death in L02 hepatocytes. The fluorescent image shows hepatocytes containing autophagosomes. For more information, see the article by Zhang and colleagues (pp. 2607–2619). The image was provided by Fang Xiao.
Research Article|
August 07 2020
Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases
Nikola Maraković;
Nikola Maraković
1Biochemistry and Organic Analytical Chemistry Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia
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Anamarija Knežević;
Anamarija Knežević
2Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia
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Igor Rončević;
Igor Rončević
3Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo náměstí 542/2, 166 10 Praha 6, Czech Republic
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Xavier Brazzolotto;
Xavier Brazzolotto
4Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 1 Place Général Valérie André, 91220 Brétigny-sur-Orge, France
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Zrinka Kovarik;
Zrinka Kovarik
1Biochemistry and Organic Analytical Chemistry Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia
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Goran Šinko
1Biochemistry and Organic Analytical Chemistry Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia
Correspondence: Goran Šinko (gsinko@imi.hr)
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Publisher: Portland Press Ltd
Received:
March 04 2020
Revision Received:
July 06 2020
Accepted:
July 08 2020
Accepted Manuscript online:
July 08 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (15): 2771–2790.
Article history
Received:
March 04 2020
Revision Received:
July 06 2020
Accepted:
July 08 2020
Accepted Manuscript online:
July 08 2020
Citation
Nikola Maraković, Anamarija Knežević, Igor Rončević, Xavier Brazzolotto, Zrinka Kovarik, Goran Šinko; Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases. Biochem J 14 August 2020; 477 (15): 2771–2790. doi: https://doi.org/10.1042/BCJ20200192
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