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QM/MM study of the catalytic reaction of potato epoxide hydrolase

Dehabadi, Maryam Haji ; Ryde, Ulf LU orcid and Irani, Mehdi LU (2026) In International Journal of Biological Macromolecules 356.
Abstract

Epoxide hydrolases are essential enzymes that convert epoxides into 1,2-diols, contributing to detoxification, metabolism, and signaling in a wide range of organisms. In this study, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to investigate the catalytic mechanism of potato epoxide hydrolase 1 (StEH1), specifically focusing on the hydrolysis of trans-stilbene oxide into chiral diols. Based on the crystal structure of StEH1 (PDB ID: 2CJP), we modeled enzyme-substrate interactions and examined the roles of the catalytic triad (Asp105, His300, and Asp265), two tyrosine residues (Tyr154 and Tyr235) involved in substrate polarization, and a crystallographic water molecule acting as the hydrolytic... (More)

Epoxide hydrolases are essential enzymes that convert epoxides into 1,2-diols, contributing to detoxification, metabolism, and signaling in a wide range of organisms. In this study, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to investigate the catalytic mechanism of potato epoxide hydrolase 1 (StEH1), specifically focusing on the hydrolysis of trans-stilbene oxide into chiral diols. Based on the crystal structure of StEH1 (PDB ID: 2CJP), we modeled enzyme-substrate interactions and examined the roles of the catalytic triad (Asp105, His300, and Asp265), two tyrosine residues (Tyr154 and Tyr235) involved in substrate polarization, and a crystallographic water molecule acting as the hydrolytic nucleophile. Our QM/MM calculations revealed a three-step reaction mechanism: alkylation, dealkylation, and proton relay. We also determined the optimal protonation states of several active-site residues, particularly His104 and His300, to ensure an accurate mechanistic picture. These results clarify previously debated aspects of the mechanism, such as the protonation state of His300 and the function of the tyrosine residues, and provide new insights into substrate specificity and offer valuable information for future efforts in inhibitor design and enzyme engineering.

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type
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publication status
published
subject
in
International Journal of Biological Macromolecules
volume
356
article number
151222
pages
17 pages
publisher
Elsevier
external identifiers
  • pmid:41794237
  • scopus:105034624026
ISSN
1879-0003
DOI
10.1016/j.ijbiomac.2026.151222
language
English
LU publication?
yes
additional info
Copyright © 2026 Elsevier B.V. All rights reserved.
id
39429a33-fa86-4bd5-9963-6e1fad5f07fc
date added to LUP
2026-04-03 09:59:13
date last changed
2026-05-28 08:36:08
@article{39429a33-fa86-4bd5-9963-6e1fad5f07fc,
  abstract     = {{<p>Epoxide hydrolases are essential enzymes that convert epoxides into 1,2-diols, contributing to detoxification, metabolism, and signaling in a wide range of organisms. In this study, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to investigate the catalytic mechanism of potato epoxide hydrolase 1 (StEH1), specifically focusing on the hydrolysis of trans-stilbene oxide into chiral diols. Based on the crystal structure of StEH1 (PDB ID: 2CJP), we modeled enzyme-substrate interactions and examined the roles of the catalytic triad (Asp105, His300, and Asp265), two tyrosine residues (Tyr154 and Tyr235) involved in substrate polarization, and a crystallographic water molecule acting as the hydrolytic nucleophile. Our QM/MM calculations revealed a three-step reaction mechanism: alkylation, dealkylation, and proton relay. We also determined the optimal protonation states of several active-site residues, particularly His104 and His300, to ensure an accurate mechanistic picture. These results clarify previously debated aspects of the mechanism, such as the protonation state of His300 and the function of the tyrosine residues, and provide new insights into substrate specificity and offer valuable information for future efforts in inhibitor design and enzyme engineering.</p>}},
  author       = {{Dehabadi, Maryam Haji and Ryde, Ulf and Irani, Mehdi}},
  issn         = {{1879-0003}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{Elsevier}},
  series       = {{International Journal of Biological Macromolecules}},
  title        = {{QM/MM study of the catalytic reaction of potato epoxide hydrolase}},
  url          = {{http://dx.doi.org/10.1016/j.ijbiomac.2026.151222}},
  doi          = {{10.1016/j.ijbiomac.2026.151222}},
  volume       = {{356}},
  year         = {{2026}},
}