Abstract
The statistical analysis is performed of changes of the bimolecular rate constant value (Δlog k II) of inhibition of human AChE, mouse AChE, AChE of flies Musca domestica and Calliphora vicina, and horse BuChE by dialkylphosphates with the general formula (AlkO) 2P(O)X at elongation of alkyl radicals and change of their branching in comparison with three physical-chemical characteristics (hydrophobicity, polarity, and volume of the side chain) of 6 amino acid residues in acyl and alkoxyl pockets variable in the studied ChE (Nos. 282, 287, 288, 290, 330, 335 in Torpedo ray AChE sequence). It has been shown that depending on structure of alkyl radicals, the rate of ChE interaction with OPI is determined by sterical hindrances to sorption (residues 282, 287, 290, 335), hydrophobic interactions (288) or polarity of microenvironment (287). This dependence in most cases is statistically significant; however, rather low values of the correlation coefficient indicate influence of structure of the OPI leaving part. The decrease of the statistical significance with elongation of alkyl radicals seems to be due to an increase of the number of possible conformational states of the OPI molecule.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Kabachnik, M.I., Brestkin, A.P., Godovikov, N.N., Michelson, M.J., Rozengart, E.V., and Rozengart, V.I., Hydrophobic Areas on Active Surface of Cholinesterases, Pharmacol. Rev., 1970, vol. 22, pp. 335–388
Hosea, N.A., Berman, H.A., and Taylor, P., Specificity and Orientation of Trigonal Carboxyl Esters and Tetrahedral Alkylphosphonyl Esters in Cholinesterases, Biochemistry, 1995, vol. 34, pp. 11 528–11 536
Harel, M., Sussman, J.L., Krejci, E., Bon, S., Chanal, P., Massoulie, J., and Silman, I., Conversion of Acetylcholinesterase to Butyrylcholinesterase: Modeling and Mutagenesis, Proc. Natl Acad. Sci. USA, 1992, vol. 89, pp. 10 827–10 831.
Ordentlich, A., Barak, D., Kronman, C., Flashner, Y., Leitner, M., Segall, Y., Ariel, N., Cohen, S., Velan, B., and Shafferman, A., Dissection of the Human Acetylcholinesterase Active Center Determinants of Substrate Specificity. Identification of Residues Constituting the Anionic Site, the Hydrophobic Site, and the Acyl Pocket, J. Biol. Chem., 1993, vol. 268, pp. 17 083–17 095.
Radic, Z., Pickering, N.A., Vellom, D.C., Camp, S., and Taylor, P., Three Distinct Domains in the Cholinesterase Molecule Confer Selectivity for Acetyl-and Butyrylcholinesterase Inhibitors, Biochemistry, 1993, vol. 32, pp. 12 074–12 084.
Ordentlich, A., Barak, D., Kronman, C., Ariel, N., Segall, Y., Velan, B., and Shafferman, A., The architecture of Human Acetylcholinesterase Active Center Probed by Interactions with Selected Organophosphate Inhibitors, J. Biol. Chem., 1996, vol. 271, pp. 11 953–11 962.
Sussman, J.L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L., and Silman, I., Atomic Structure of Acetylcholinesterase from Torpedo californica: A Prototypic Acetylcholine-Binding Protein, Science, 1991, vol. 253, pp. 872–879.
Felder, C.E. and Sussman, J.L., Homology-Built Model of Human Acetylcholinesterase, Unpublished.
Bourne, Y., Taylor, P., Bougis, P.E., and Marchot, P., Crystal Structure of Mouse Acetylcholinesterase. A Peripheral Site-Occluding Loop in a Tetrameric Assembly, J. Biol. Chem., 1999, vol. 274, pp. 2963–2970.
Harel, M., Kryger, G., Rosenberry, T.L., Mallender, W.D., Lewis, T., Fletcher, R.J., Guss, J.M., Silman, I., and Sussman, J.L., Three-Dimensional Structures of Drosophila melanogaster Acetylcholinesterase and of Its Complexes with Two Potent Inhibitors, Protein Science, 2000, vol. 9, pp. 1063–1072.
Moralev, S.N. and Rozengart, E.V., Current Concepts of Structure and Catalytic Properties of Vertebrate and Invertebrate Cholinesterases, Zh. Evol. Biokhim. Fiziol., 1999, vol. 35, pp. 3–15.
Moralev S.N. and Bazyukin, A.B., Use of the Multidimensional Statistical Analysis in Study of Dependence of Anticholinesterase Potency of Organophosphorus Inhibitors on Their Structure, Zh. Evol. Biokhim. Fiziol., 1997, vol. 33, pp. 302–306.
Cousin, X., Hotelier, T., Giles, K., Toutant, J.P., and Chatonnet, A., aCHEdb: The Database System for ESTHER, the Alpha/beta Fold Family of Proteins and the Cholinesterase Gene Server, Nucl. Acids Res., 1998, vol. 26, pp. 226–228.
Kugusheva, L.I., Dalimov, D.N., Moralev, S.N., Prokhorenko, N.K., Babaev, B.N., and Abduvakhabov, A.A., Interaction of Cholinesterases and Carboxylesterases of Mammals and Arthropods with O,O-dialkyl-S-propargyl Thiophosphates, Uzbek. Khim. Zh., 1990, no. 3, pp. 40–43.
Balashova, E.K., Brestkin, A.P., Zhukovskii, Yu.G., Rozengart, V.I., Sherstobitov, O.E., Vasil'eva, T.P., Savchenko, K.N., Abduvakhabov, A.A., and Dalimov, D.N., Effects of Organophosphorus Inhibitors, Derivatives of Lupinine and Epilupinine, on Cholinesterases of Mammals and Arthropods, Zh. Evol. Biokhim. Fiziol., 1980, vol. 16, pp. 244–250.
Godovikov, N.N., Vikhreva, L.A., Darisheva, A.L., Balashova, E.K., Moralev, S.N., Brestkin, A.P., Rozengart, V.I., Sherstobitov, O.E., and Kabachnik, M.I., Synthesis and Anticholinesterase Activity of S-ethynyl Esters of Dialkylthiophosphoric Acids with Cyclic Substitutions at the Acetylene Bond, Izv. Akad. Nauk SSSR, Ser. Khim., 1987, no. 1, pp. 170–176.
Vikhreva, L.A., Pudova, T.A., Godovikov, N.N., Roslavtseva, S.A., Balashova, E.K., Rozengart, V.I., and Sherstobitov, O.E., Biological Activity of S-butynyl Esters of Phosphorus Thioacids, Khimiya fiziologicheski aktivnykh veshchestv. Tematicheskii mezhvuzovskii sbornik (Chemistry of Physiologically Active Compounds, The Thematic Inter-University Work Collection), Issue 3, Nal'chik, 1980, pp. 118–123.
Shataeva, G.A., Makhaeva, G.F., Yankovskaya, V.L., Sokolov, V.B., Ivanov, A.N., and Martynov, I.V., Comparative Study of Sensitivity of Acetylcholinesterases from Human Erythrocytes and House Fly Heads to Phosphorylated Alkylchloroformoximes, Zh. Evol. Biokhim. Fiziol., 1988, vol. 24, pp. 791–795.
Shustova, V.P., Khaskin, B.A., Sheluchenko, O.D., Roslavtseva, S.A., Torgasheva, N.A., and Kheiman, V.A., Bis-(dialkoxythiophosphorylthio) methanes and Dialkoxythiophosphoryloxydialkoxyphosphorylthiomethanes and Their Anticholinesterase Activity, Pestitsidy i ikh primenenie (Pesticides and Their Application), Moscow, 1982, pp. 23–29.
Metcalf, R.L., March, R.B., and Maxon, M.G., Substrate Preferences of Insect Cholinesterases, Ann. Entom. Soc. Amer., 1955, vol. 48, pp. 222–228.
Grigor'eva, G.M., Krasnova, T.I., Khovanskikh, A.E., and Lezhneva, I.L., Substrate and Inhibitor Specificity of Brain Cholinesterase from Different Species of Flies (Diptera: Anthomiidae, Muscidae). On the Problem of the Enzyme Type, Zh. Evol. Biokhim. Fiziol., 1997, vol. 33, pp. 431–442.
Eisenberg, D., Schwarz, E., Komaromy, M., and Wall, R., Analysis of Membrane and Surface Protein Sequences with the Hydrophobic Moment Plot, J. Mol. Biol., 1984, vol. 179, pp. 125–142.
Woese, C.R, Dugre, D.H, Dugre, S.A., Kondo, M., and Saxinger, W.C., On the Fundamental Nature and Evolution of the Genetic Code, Cold Spring Harbor Symp. Quant. Biol., 1966, vol. 31, pp. 723–736.
Creighton, T.E., Proteins. Structural and Molecular Properties, New York: Freeman, 1992, p. 143.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moralev, S.N. Acyl Pocket of the Cholinesterase Active Center and Dialkylphosphates: Study of Interaction by Statistical Methods. Journal of Evolutionary Biochemistry and Physiology 37, 121–132 (2001). https://doi.org/10.1023/A:1017676729062
Issue Date:
DOI: https://doi.org/10.1023/A:1017676729062