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Electrostatic attraction by surface charge does not contribute to the catalytic efficiency of acetylcholinesterase.

1994; Springer Nature; Volume: 13; Issue: 15 Linguagem: Inglês

10.1002/j.1460-2075.1994.tb06650.x

1460-2075

Avigdor Shafferman, Arie Ordentlich, Dov Barak, C. Kronman, Raphael Ber, Tamar Bino, Naomi Ariel, Roman Osman, Baruch Velan,

Computational Drug Discovery Methods

Research Article1 August 1994free access Electrostatic attraction by surface charge does not contribute to the catalytic efficiency of acetylcholinesterase. A. Shafferman A. Shafferman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author A. Ordentlich A. Ordentlich Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author D. Barak D. Barak Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author C. Kronman C. Kronman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author R. Ber R. Ber Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author T. Bino T. Bino Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author N. Ariel N. Ariel Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author R. Osman R. Osman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author B. Velan B. Velan Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author A. Shafferman A. Shafferman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author A. Ordentlich A. Ordentlich Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author D. Barak D. Barak Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author C. Kronman C. Kronman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author R. Ber R. Ber Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author T. Bino T. Bino Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author N. Ariel N. Ariel Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author R. Osman R. Osman Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author B. Velan B. Velan Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. Search for more papers by this author Author Information A. Shafferman1, A. Ordentlich1, D. Barak1, C. Kronman1, R. Ber1, T. Bino1, N. Ariel1, R. Osman1 and B. Velan1 1Department of Biochemistry, Israel Institute for Biological Research, Ness-Ziona. The EMBO Journal (1994)13:3448-3455https://doi.org/10.1002/j.1460-2075.1994.tb06650.x PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Acetylcholinesterases (AChEs) are characterized by a high net negative charge and by an uneven surface charge distribution, giving rise to a negative electrostatic potential extending over most of the molecular surface. To evaluate the contribution of these electrostatic properties to the catalytic efficiency, 20 single- and multiple-site mutants of human AChE were generated by replacing up to seven acidic residues, vicinal to the rim of the active-center gorge (Glu84, Glu285, Glu292, Asp349, Glu358, Glu389 and Asp390), by neutral amino acids. Progressive simulated replacement of these charged residues results in a gradual decrease of the negative electrostatic potential which is essentially eliminated by neutralizing six or seven charges. In marked contrast to the shrinking of the electrostatic potential, the corresponding mutations had no significant effect on the apparent bimolecular rate constants of hydrolysis for charged and non-charged substrates, or on the Ki value for a charged active center inhibitor. Moreover, the kcat values for all 20 mutants are essentially identical to that of the wild type enzyme, and the apparent bimolecular rate constants show a moderate dependence on the ionic strength, which is invariant for all the enzymes examined. These findings suggest that the surface electrostatic properties of AChE do not contribute to the catalytic rate, that this rate is probably not diffusion-controlled and that long-range electrostatic interactions play no role in stabilization of the transition states of the catalytic process. Previous ArticleNext Article Volume 13Issue 151 August 1994In this issue RelatedDetailsLoading ...