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Title: Role of active site tyrosine in glutathione S-transferase: Insights from a theoretical study on model systems

Abstract

Ab initio molecular orbital theory was used to examine the role of active site tyrosine in glutathione 4-transferases by using appropriate model systems. The location of the key mechanistic proton of the enzyme-glutathione binary complex, O- - -H- - -S, was predicted to be near the phenolic oxygen, which is in agreement with experiments. However, the position of the proton can be manipulated by changing the acidity of the tyrosine, which can be accomplished by either introducing a substituent group to the tyrosine phenol ring or changing the protein environment. Thus, our study seems to have resolved previous confusion as to where the proton is located. The hydrogen bonding between tyrosine and thiolate of glutathione is very strong. On the basis of our present study, we propose that, in the Y6F (Tyr {yields} Phe) mutant, a water molecule replaces the function of the hydroxyl group of the active site tyrosine of the wild-type enzyme. Several lines of evidence in support of the above hypothesis are discussed. The latter hypothesis is reminiscent of the notion of substrate-assisted catalysis. 43 refs., 3 figs., 2 tabs.

Authors:
;  [1]
  1. Pacific Northwest National Lab., Richland, WA (United States)
Publication Date:
OSTI Identifier:
466313
DOE Contract Number:  
AC06-76RL01830
Resource Type:
Journal Article
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 119; Journal Issue: 7; Other Information: PBD: 19 Feb 1997
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; 40 CHEMISTRY; 99 MATHEMATICS, COMPUTERS, INFORMATION SCIENCE, MANAGEMENT, LAW, MISCELLANEOUS; PROTEINS; STRUCTURAL CHEMICAL ANALYSIS; TYROSINE; ENZYMES; COMPLEXES; PROTONS; TRANSFERASES; HARTREE-FOCK METHOD; MOLECULAR MODELS; GEOMETRY; MOLECULAR ORBITAL METHOD

Citation Formats

Zheng, Y.J., and Ornstein, R.L. Role of active site tyrosine in glutathione S-transferase: Insights from a theoretical study on model systems. United States: N. p., 1997. Web. doi:10.1021/ja961667h.
Zheng, Y.J., & Ornstein, R.L. Role of active site tyrosine in glutathione S-transferase: Insights from a theoretical study on model systems. United States. doi:10.1021/ja961667h.
Zheng, Y.J., and Ornstein, R.L. Wed . "Role of active site tyrosine in glutathione S-transferase: Insights from a theoretical study on model systems". United States. doi:10.1021/ja961667h.
@article{osti_466313,
title = {Role of active site tyrosine in glutathione S-transferase: Insights from a theoretical study on model systems},
author = {Zheng, Y.J. and Ornstein, R.L.},
abstractNote = {Ab initio molecular orbital theory was used to examine the role of active site tyrosine in glutathione 4-transferases by using appropriate model systems. The location of the key mechanistic proton of the enzyme-glutathione binary complex, O- - -H- - -S, was predicted to be near the phenolic oxygen, which is in agreement with experiments. However, the position of the proton can be manipulated by changing the acidity of the tyrosine, which can be accomplished by either introducing a substituent group to the tyrosine phenol ring or changing the protein environment. Thus, our study seems to have resolved previous confusion as to where the proton is located. The hydrogen bonding between tyrosine and thiolate of glutathione is very strong. On the basis of our present study, we propose that, in the Y6F (Tyr {yields} Phe) mutant, a water molecule replaces the function of the hydroxyl group of the active site tyrosine of the wild-type enzyme. Several lines of evidence in support of the above hypothesis are discussed. The latter hypothesis is reminiscent of the notion of substrate-assisted catalysis. 43 refs., 3 figs., 2 tabs.},
doi = {10.1021/ja961667h},
journal = {Journal of the American Chemical Society},
number = 7,
volume = 119,
place = {United States},
year = {1997},
month = {2}
}