Effects of volume and surface property in hydrolysis by acetylcholinesterase. The trimethyl site

• Published in: Journal of medicinal chemistry Vol. 27; no. 12; pp. 1643 - 1647
• Main Authors: Cohen, Saul G, Elkind, Jerome L, Chishti, S. Bano, Giner, Jose L, Reese, Heide
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.1984
• Subjects: Acetates - chemical synthesis; Acetylcholinesterase - metabolism; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Chemical Phenomena; Chemistry; Electrophorus; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Hydrolysis; Indicators and Reagents; Kinetics; Magnetic Resonance Spectroscopy; Structure-Activity Relationship; Substrate Specificity; Surface Properties; Subsite; Vertebrata; Synthetic substrate; Enzyme; Pisces; Active site; Substrate specificity; Surface properties; Hydrophobicity; Acetylcholinesterase; Chemical reactivity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00378a020

beta-Substituted ethyl acetates, XCH2CH2OCOCH3, have been prepared, and their hydrolysis by acetylcholinesterase has been studied. Log of enzymic reactivity, normalized for intrinsic reactivity in hydrolysis by hydroxide, log (kcat/Km)n, rises linearly with increasing refraction volume, MR (or RD25), for substrates with beta-X = H, Cl, Br, CH3CH2, (CH3)2CH, (CH3)2S+, (CH3)3N+, and (CH3)3C. Larger substituents may be accommodated, (CH3)3Si and (CH3CH2)3N+, with no further increase in rate. Substrates with beta-substituents CH3S, CH3S(O), (CH3)3N+(OH), and CH3S(O2) are less reactive than consistent with the relation with MR by factors of 5-40, indicating that hydrophobic surface and desolvation of the substrate--enzyme interface may be necessary for maximum reactivity correlated with MR. Values of log (kcat/Km)n for substrates with beta-substituents X = CH3S, Cl, Br, CH3CH2, (CH3)2CH, (CH3)3C, and (CH3)3Si rise linearly with increasing hydrophobicity, pi, but reactivity of substrates with X = (CH3)3N+ and (CH3)2S+ are more reactive than consistent with a relation to pi by factors of 300 and 40 and with X = CH3S(O2), CH3S(O), and (CH3)2N+(OH), by factors of 7-100. Reactivity appears related to (i) volume of the beta-substituent and its fit in its subsite, which is trimethyl rather than anionic, and (ii) the hydrophobicity of its surface.