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Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.

Carletti E, Aurbek N, Gillon E, Loiodice M, Nicolet Y, Fontecilla-Camps JC, Masson P, Thiermann H, Nachon F, Worek F
Biochem J 421 97-106 (2009)
Related entries: 2wid, 2wif, 2wig, 2wij, 2wik, 2wsl

Cited: 39 times
EuropePMC logo PMID: 19368529

Abstract

hBChE [human BChE (butyrylcholinesterase)] naturally scavenges OPs (organophosphates). This bioscavenger is currently in Clinical Phase I for pretreatment of OP intoxication. Phosphylated ChEs (cholinesterases) can undergo a spontaneous time-dependent process called 'aging' during which the conjugate is dealkylated, leading to creation of an enzyme that cannot be reactivated. hBChE inhibited by phosphoramidates such as tabun displays a peculiar resistance to oxime-mediated reactivation. We investigated the basis of oxime resistance of phosphoramidyl-BChE conjugates by determining the kinetics of inhibition, reactivation (obidoxime {1,1'-(oxybis-methylene) bis[4-(hydroxyimino) methyl] pyridinium dichloride}, TMB-4 [1,3-trimethylene-bis(4-hydroxyiminomethylpyridinium) dibromide], HLö 7 {1-[[[4-(aminocarbonyl) pyridinio]methoxy]methyl]-2,4-bis-[(hydroxyimino)methyl] pyridinium dimethanesulfonate)}, HI-6 {1-[[[4-(aminocarbonyl) pyridinio] methoxy] methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride monohydrate} and aging, and the crystal structures of hBChE inhibited by different N-monoalkyl and N,N-dialkyl tabun analogues. The refined structures of aged hBChE conjugates show that aging proceeds through O-dealkylation of the P(R) enantiomer of N,N-diethyl and N-propyl analogues, with subsequent formation of a salt bridge preventing reactivation, similarly to a previous observation made on tabun-ChE conjugates. Interestingly, the N-methyl analogue projects its amino group towards the choline-binding pocket, so that aging proceeds through deamination. This orientation results from a preference of hBChE's acyl-binding pocket for larger than 2-atoms linear substituents. The correlation between the inhibitory potency and the N-monoalkyl chain length is related to increasingly optimized interactions with the acyl-binding pocket as shown by the X-ray structures. These kinetics and X-ray data lead to a structure-activity relationship that highlights steric and electronic effects of the amino substituent of phosphoramidate. This study provides the structural basis to design new oximes capable of reactivating phosphoramidyl-hBChE conjugates after intoxication, notably when hBChE is used as pretreatment, or to design BChE-based catalytic bioscavengers.

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Reviews citing this publication (7)

  1. Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior. Masson P, Lockridge O. Arch Biochem Biophys 494 107-120 (2010)
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  10. Reactivation of tabun-hAChE investigated by structurally analogous oximes and mutagenesis. Artursson E, Akfur C, Hörnberg A, Worek F, Ekström F. Toxicology 265 108-114 (2009)
  11. A step toward the reactivation of aged cholinesterases--crystal structure of ligands binding to aged human butyrylcholinesterase. Wandhammer M, de Koning M, van Grol M, Loiodice M, Saurel L, Noort D, Goeldner M, Nachon F. Chem Biol Interact 203 19-23 (2013)
  12. Why does the G117H mutation considerably improve the activity of human butyrylcholinesterase against sarin? Insights from quantum mechanical/molecular mechanical free energy calculations. Yao Y, Liu J, Zhan CG. Biochemistry 51 8980-8992 (2012)
  13. Aging mechanism of butyrylcholinesterase inhibited by an N-methyl analogue of tabun: implications of the trigonal-bipyramidal transition state rearrangement for the phosphylation or reactivation of cholinesterases. Nachon F, Carletti E, Worek F, Masson P. Chem Biol Interact 187 44-48 (2010)
  14. Enzyme-linked immunosorbent assay for detection of organophosphorylated butyrylcholinesterase: a biomarker of exposure to organophosphate agents. Wang L, Du D, Lu D, Lin CT, Smith JN, Timchalk C, Liu F, Wang J, Lin Y. Anal Chim Acta 693 1-6 (2011)
  15. High-Confidence Qualitative Identification of Organophosphorus Nerve Agent Adducts to Human Butyrylcholinesterase. Mathews TP, Carter MD, Johnson D, Isenberg SL, Graham LA, Thomas JD, Johnson RC. Anal Chem 89 1955-1964 (2017)
  16. Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae). Wan Othman WNN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K. Bioorg Med Chem 24 4464-4469 (2016)
  17. New cholinesterase inhibitors from Garcinia atroviridis. Tan WN, Khairuddean M, Wong KC, Khaw KY, Vikneswaran M. Fitoterapia 97 261-267 (2014)
  18. Reactivation kinetics of 31 structurally different bispyridinium oximes with organophosphate-inhibited human butyrylcholinesterase. Horn G, Wille T, Musilek K, Kuca K, Thiermann H, Worek F. Arch Toxicol 89 405-414 (2015)
  19. Kinetic analysis of interactions of different sarin and tabun analogues with human acetylcholinesterase and oximes: is there a structure-activity relationship? Aurbek N, Herkert NM, Koller M, Thiermann H, Worek F. Chem Biol Interact 187 215-219 (2010)
  20. Novel bisquaternary oximes--reactivation of acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon. Kuca K, Musilova L, Palecek J, Cirkva V, Paar M, Musilek K, Hrabinova M, Pohanka M, Karasova JZ, Jun D. Molecules 14 4915-4921 (2009)
  21. Salicylanilide diethyl phosphates as cholinesterases inhibitors. Krátký M, Štěpánková Š, Vorčáková K, Vinšová J. Bioorg Chem 58 48-52 (2015)
  22. Pyridoxal oxime derivative potency to reactivate cholinesterases inhibited by organophosphorus compounds. Bušić V, Katalinić M, Šinko G, Kovarik Z, Gašo-Sokač D. Toxicol Lett 262 114-122 (2016)
  23. Online coupling of immunoextraction, digestion, and microliquid chromatography-tandem mass spectrometry for the analysis of sarin and soman-butyrylcholinesterase adducts in human plasma. Bonichon M, Valbi V, Combès A, Desoubries C, Bossée A, Pichon V. Anal Bioanal Chem 410 1039-1051 (2018)
  24. Mass spectrometry method to identify aging pathways of Sp- and Rp-tabun adducts on human butyrylcholinesterase based on the acid labile P-N bond. Jiang W, Cashman JR, Nachon F, Masson P, Schopfer LM, Lockridge O. Toxicol Sci 132 390-398 (2013)
  25. 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)
  26. 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)
  27. Multiple resistance to pirimiphos-methyl and bifenthrin in Tribolium castaneum involves the activity of lipases, esterases, and laccase2. Julio AH, Gigliolli AA, Cardoso KA, Drosdoski SD, Kulza RA, Seixas FA, Ruvolo-Takasusuki MC, de Souza CG, Lapenta AS. Comp Biochem Physiol C Toxicol Pharmacol 195 27-43 (2017)
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  29. Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon. Kuca K, Jun D, Junova L, Musilek K, Hrabinova M, da Silva JAV, Ramalho TC, Valko M, Wu Q, Nepovimova E, França TCC. Molecules 23 E1103 (2018)
  30. A color-reaction-based rapid screening for null activity of butyrylcholinesterase: a step toward point-of-care screening for succinylcholine apnea. Nagpal N, Chowdhary S, Bhattacharyya R, Banerjee D. Biotechnol Appl Biochem 62 154-163 (2015)
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