Effects of Volume and Surface Property in Hydrolysis by Acetylcholinesterase. The Trimethyl Site

Saul G. Cohen; Jerome L. Elkind; S. Bano Chishti; Jose L.P. Giner; Heide Reese; Jonathan B. Cohen

doi:10.1021/jm00378a020

Effects of Volume and Surface Property in Hydrolysis by Acetylcholinesterase. The Trimethyl Site

Saul G. Cohen
, Jerome L. Elkind
, S. Bano Chishti
, Jose L.P. Giner
, Heide Reese
, Jonathan B. Cohen

Chemistry

College of Environmental Science & Forestry

Brandeis University
Washington University St. Louis

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

β-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 (k_cat/K_m)_n, rises linearly with increasing refraction volume, MR (or RD²⁵), for substrates with β-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 β-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 (k_cat/k_m)_n for substrates with β-substituents X = CH₃S, Cl, Br, CH₃CH₂, (CH₃)₂CH, (CH₃)₃C, and (CH₃)₃Si rise linearly with increasing hydrophobicity, π, but reactivity of substrates with X = (CH₃)₃N⁺ and (CH₃)₂S⁺ are more reactive than consistent with a relation to π 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 β-substituent and its fit in its subsite, which is trimethyl rather than anionic, and (ii) the hydrophobicity of its surface.

Original language	English
Pages (from-to)	1643-1647
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	27
Issue number	12
DOIs	https://doi.org/10.1021/jm00378a020
State	Published - Feb 1984

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@article{f6daaf21e3634fae8a6629d78a1f3f22,

title = "Effects of Volume and Surface Property in Hydrolysis by Acetylcholinesterase. The Trimethyl Site",

abstract = "β-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 β-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 β-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 β-substituents X = CH3S, Cl, Br, CH3CH2, (CH3)2CH, (CH3)3C, and (CH3)3Si rise linearly with increasing hydrophobicity, π, but reactivity of substrates with X = (CH3)3N+ and (CH3)2S+ are more reactive than consistent with a relation to π 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 β-substituent and its fit in its subsite, which is trimethyl rather than anionic, and (ii) the hydrophobicity of its surface.",

author = "Cohen, \{Saul G.\} and Elkind, \{Jerome L.\} and Chishti, \{S. Bano\} and Giner, \{Jose L.P.\} and Heide Reese and Cohen, \{Jonathan B.\}",

year = "1984",

month = feb,

doi = "10.1021/jm00378a020",

language = "English",

volume = "27",

pages = "1643--1647",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

number = "12",

}

TY - JOUR

T1 - Effects of Volume and Surface Property in Hydrolysis by Acetylcholinesterase. The Trimethyl Site

AU - Cohen, Saul G.

AU - Elkind, Jerome L.

AU - Chishti, S. Bano

AU - Giner, Jose L.P.

AU - Reese, Heide

AU - Cohen, Jonathan B.

PY - 1984/2

Y1 - 1984/2

N2 - β-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 β-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 β-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 β-substituents X = CH3S, Cl, Br, CH3CH2, (CH3)2CH, (CH3)3C, and (CH3)3Si rise linearly with increasing hydrophobicity, π, but reactivity of substrates with X = (CH3)3N+ and (CH3)2S+ are more reactive than consistent with a relation to π 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 β-substituent and its fit in its subsite, which is trimethyl rather than anionic, and (ii) the hydrophobicity of its surface.

AB - β-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 β-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 β-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 β-substituents X = CH3S, Cl, Br, CH3CH2, (CH3)2CH, (CH3)3C, and (CH3)3Si rise linearly with increasing hydrophobicity, π, but reactivity of substrates with X = (CH3)3N+ and (CH3)2S+ are more reactive than consistent with a relation to π 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 β-substituent and its fit in its subsite, which is trimethyl rather than anionic, and (ii) the hydrophobicity of its surface.

UR - https://www.scopus.com/pages/publications/0021713301

U2 - 10.1021/jm00378a020

DO - 10.1021/jm00378a020

M3 - Article

C2 - 6502594

SN - 0022-2623

VL - 27

SP - 1643

EP - 1647

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 12

ER -

Effects of Volume and Surface Property in Hydrolysis by Acetylcholinesterase. The Trimethyl Site

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