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Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface.

Franklin MC, Rudolph MJ, Ginter C, Cassidy MS, Cheung J
Proteins 84 1246-56 (2016)
Related entries: 5hf5, 5hf6, 5hf8, 5hf9

Cited: 39 times
EuropePMC logo PMID: 27191504

Abstract

Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. © 2016 Wiley Periodicals, Inc.

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  1. Metal based donepezil analogues designed to inhibit human acetylcholinesterase for Alzheimer's disease. Junaid M, Islam N, Hossain MK, Ullah MO, Halim MA. PLoS One 14 e0211935 (2019)
  2. Study on Synergistic Antioxidant Effect of Typical Functional Components of Hydroethanolic Leaf Extract from Ginkgo Biloba In Vitro. Zhang L, Zhu C, Liu X, Su E, Cao F, Zhao L. Molecules 27 439 (2022)
  3. Inhibitory Effects of Cannabinoids on Acetylcholinesterase and Butyrylcholinesterase Enzyme Activities. Puopolo T, Liu C, Ma H, Seeram NP. Med Cannabis Cannabinoids 5 85-94 (2022)
  4. Neuroprotective potential of terpenoid-rich extracts from orange juice by-products obtained by pressurized liquid extraction. Sánchez-Martínez JD, Alvarez-Rivera G, Gallego R, Fagundes MB, Valdés A, Mendiola JA, Ibañez E, Cifuentes A. Food Chem X 13 100242 (2022)
  5. Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon. de Paula RL, de Almeida JSFD, Cavalcante SFA, Gonçalves AS, Simas ABC, Franca TCC, Valis M, Kuca K, Nepovimova E, Granjeiro JM. Molecules 23 E2954 (2018)
  6. Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase. Jończyk J, Kukułowicz J, Łątka K, Malawska B, Jung YS, Musilek K, Bajda M. Biomolecules 11 169 (2021)
  7. New carvacrol and thymol derivatives as potential insecticides: synthesis, biological activity, computational studies and nanoencapsulation. Natal CM, Fernandes MJG, Pinto NFS, Pereira RB, Vieira TF, Rodrigues ARO, Pereira DM, Sousa SF, Fortes AG, Castanheira EMS, T Gonçalves MS. RSC Adv 11 34024-34035 (2021)
  8. Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning. Gambino A, Burnett JC, Koide K. ACS Med Chem Lett 11 1893-1898 (2020)
  9. Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates. Lee HM, Andrys R, Jonczyk J, Kim K, Vishakantegowda AG, Malinak D, Skarka A, Schmidt M, Vaskova M, Latka K, Bajda M, Jung YS, Malawska B, Musilek K. J Enzyme Inhib Med Chem 36 437-449 (2021)
  10. Design of electron-donating group substituted 2-PAM analogs as antidotes for organophosphate insecticide poisoning. Kongkaew N, Hengphasatporn K, Injongkol Y, Mee-Udorn P, Shi L, Mahalapbutr P, Maitarad P, Harada R, Shigeta Y, Rungrotmongkol T, Vangnai AS. RSC Adv 13 32266-32275 (2023)
  11. Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators. Kitagawa DAS, Rodrigues RB, Silva TN, Dos Santos WV, da Rocha VCV, de Almeida JSFD, Bernardo LB, Carvalho-Silva T, Ferreira CN, da Silva AAT, Simas ABC, Nepovimova E, Kuča K, França TCC, Cavalcante SFA. J Enzyme Inhib Med Chem 36 1370-1377 (2021)
  12. Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation. Cannon J, Tang S, Yang K, Harrison R, Choi SK. RSC Med Chem 12 1592-1603 (2021)
  13. Novel uncharged triazole salicylaldoxime derivatives as potential acetylcholinesterase reactivators: comprehensive computational study, synthesis and in vitro evaluation. Baghersad MH, Habibi A, Dehdashti Nejad A. RSC Adv 13 28527-28541 (2023)
  14. Tsaokoic Acid: A New Bicyclic Nonene from the Fruits of Amomum tsao-ko with Acetylcholinesterase Inhibitory Activity. Kim H, Lee H, Jung HJ, Noh SG, Youn I, Kwak H, Lee Y, Nam SJ, Kang S, Chung HY, Seo EK. Molecules 28 2602 (2023)


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  2. Recent developments in structural studies on acetylcholinesterase. Silman I, Sussman JL. J Neurochem 142 Suppl 2 19-25 (2017)
  3. Non-conventional compounds with potential therapeutic effects against Alzheimer's disease. de Castro AA, Soares FV, Pereira AF, Polisel DA, Caetano MS, Leal DHS, da Cunha EFF, Nepovimova E, Kuca K, Ramalho TC. Expert Rev Neurother 19 375-395 (2019)
  4. Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X-ray structures. Radić Z. J Neurochem (2023)
  5. Rate-limiting step in the decarbamoylation of acetylcholinesterases with large carbamoyl groups. Rosenberry TL, Cheung J. Chem Biol Interact 308 392-395 (2019)

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  2. Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance. Cheung J, Mahmood A, Kalathur R, Liu L, Carlier PR. Structure 26 130-136.e2 (2018)
  3. Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration. Zorbaz T, Braïki A, Maraković N, Renou J, de la Mora E, Maček Hrvat N, Katalinić M, Silman I, Sussman JL, Mercey G, Gomez C, Mougeot R, Pérez B, Baati R, Nachon F, Weik M, Jean L, Kovarik Z, Renard PY. Chemistry 24 9675-9691 (2018)
  4. From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease. Chierrito TPC, Pedersoli-Mantoani S, Roca C, Requena C, Sebastian-Perez V, Castillo WO, Moreira NCS, Pérez C, Sakamoto-Hojo ET, Takahashi CS, Jiménez-Barbero J, Cañada FJ, Campillo NE, Martinez A, Carvalho I. Eur J Med Chem 139 773-791 (2017)
  5. Identification of new allosteric sites and modulators of AChE through computational and experimental tools. Roca C, Requena C, Sebastián-Pérez V, Malhotra S, Radoux C, Pérez C, Martinez A, Antonio Páez J, Blundell TL, Campillo NE. J Enzyme Inhib Med Chem 33 1034-1047 (2018)
  6. Rational design, synthesis, and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. Gorecki L, Gerlits O, Kong X, Cheng X, Blumenthal DK, Taylor P, Ballatore C, Kovalevsky A, Radić Z. J Biol Chem 295 4079-4092 (2020)
  7. Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase. Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radić Z, Kovalevsky A. J Biol Chem 294 10607-10618 (2019)
  8. Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers. Wong PT, Bhattacharjee S, Cannon J, Tang S, Yang K, Bowden S, Varnau V, O'Konek JJ, Choi SK. Org Biomol Chem 17 3951-3963 (2019)
  9. Decarbamoylation of acetylcholinesterases is markedly slowed as carbamoyl groups increase in size. Venkatasubban KS, Johnson JL, Thomas JL, Fauq A, Cusack B, Rosenberry TL. Arch Biochem Biophys 655 67-74 (2018)
  10. Efficient synthesis of novel dialkyl-3-cyanopropylphosphate derivatives and evaluation of their anticholinesterase activity. Aouani I, Sellami B, Lahbib K, Cavalier JF, Touil S. Bioorg Chem 72 301-307 (2017)
  11. Room temperature crystallography of human acetylcholinesterase bound to a substrate analogue 4K-TMA: Towards a neutron structure. Gerlits O, Blakeley MP, Keen DA, Radić Z, Kovalevsky A. Curr Res Struct Biol 3 206-215 (2021)
  12. The structural and biochemical impacts of monomerizing human acetylcholinesterase. Bester SM, Adipietro KA, Funk VL, Myslinski JM, Keul ND, Cheung J, Wilder PT, Wood ZA, Weber DJ, Height JJ, Pegan SD. Protein Sci 28 1106-1114 (2019)
  13. Covalent inhibition of hAChE by organophosphates causes homodimer dissociation through long-range allosteric effects. Blumenthal DK, Cheng X, Fajer M, Ho KY, Rohrer J, Gerlits O, Taylor P, Juneja P, Kovalevsky A, Radić Z. J Biol Chem 297 101007 (2021)
  14. Mechanical Bond Approach to Introducing Self-Adaptive Active Sites in Covalent Organic Frameworks for Zinc-Catalyzed Organophosphorus Degradation. Ruan X, Yang Y, Liu W, Ma X, Zhang C, Meng Q, Wang Z, Cui F, Feng J, Cai F, Yuan Y, Zhu G. ACS Cent Sci 7 1698-1706 (2021)
  15. Solvent Deuterium Oxide Isotope Effects on the Reactions of Organophosphorylated Acetylcholinesterase. Rosenberry TL. Molecules 25 E4412 (2020)
  16. Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering. Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radić Z, Kovalevsky A. Structure 30 1538-1549.e3 (2022)
  17. New Myrtenal-Adamantane Conjugates Alleviate Alzheimer's-Type Dementia in Rat Model. Dragomanova S, Lazarova M, Munkuev A, Suslov E, Volcho K, Salakhutdinov N, Bibi A, Reynisson J, Tzvetanova E, Alexandrova A, Georgieva A, Uzunova D, Stefanova M, Kalfin R, Tancheva L. Molecules 27 5456 (2022)
  18. Response Surface Study on Molecular Docking Simulations of Citalopram and Donepezil as Potent CNS Drugs. Alikhani R, Ebadi A, Karami P, Shahbipour S, Razzaghi-Asl N. Iran J Pharm Res 20 560-576 (2021)


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