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Exploring the substrate selectivity of human sEH and M. tuberculosis EHB using QM/MM

Sandra Rabi, Anand HG Patel, Steven K Burger, Toon Verstraelen UGent and Paul W Ayers (2017) STRUCTURAL CHEMISTRY. 28(5). p.1501-1511
abstract
The mechanisms of human soluble epoxide hydrolase (sEH) and the corresponding epoxide hydrolase enzyme from Mycobacterium tuberculosis (EHB) are studied computationally, using the quantum mechanics/molecular mechanics (QM/MM) method. To do this, we modeled the alkylation and the hydrolysis steps of three substrates: trans-1,3-diphenylpropene oxide, trans-stilbene oxide and cis-stilbene oxide. Studying the regioselectivity for trans-1,3-diphenylpropene oxide, we determined that both enzymes prefer ring opening via attack on the benzylic carbon. In agreement with experimental studies, our computations show that the rate-limiting step is hydrolysis of the ester intermediate, with reaction barriers of approximately 13 to 18 kcal/mol. Using the barrier energies of this rate-limiting step, the three epoxides were ranked in order of reactivity. Though the reactivity order was correctly predicted for sEH, the predicted order for EHB did not correspond to experimental observations. Next, the electrostatic contributions of individual residues on the barrier height of the rate-limiting step were also studied. This revealed several residues important for catalysis. The secondary tritium kinetic isotope effect for the alkylation step was determined using a cluster model for the active site of sEH. The calculated value was 1.27, suggesting a late transition state for the rate-limiting step. Finally, we analyzed the reactivity trends using reactivity indicators from conceptual density functional theory, allowing us to identify ease of electron transfer as the primary driving force for the reaction.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Epoxide hydrolase mechanism, QM/MM, Tuberculosis antibiotics, sEH, Epoxide hydrolase B, SOLUBLE EPOXIDE HYDROLASE, MOLECULAR-ORBITAL METHODS, EXTENDED BASIS-SETS, VALENCE BASIS-SETS, MINIMUM POLARIZABILITY PRINCIPLES, NONTOTALLY SYMMETRIC VIBRATIONS, DENSITY-FUNCTIONAL-APPROACH, FRONTIER-ELECTRON THEORY, TRANSITION-STATE THEORY, CHEMICAL-REACTIVITY
journal title
STRUCTURAL CHEMISTRY
Struct. Chem.
volume
28
issue
5
pages
1501 - 1511
Web of Science type
Article
Web of Science id
000409518700024
ISSN
1040-0400
1572-9001
DOI
10.1007/s11224-017-0982-3
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8532329
handle
http://hdl.handle.net/1854/LU-8532329
date created
2017-09-26 12:54:41
date last changed
2017-11-09 09:54:56
@article{8532329,
  abstract     = {The mechanisms of human soluble epoxide hydrolase (sEH) and the corresponding epoxide hydrolase enzyme from Mycobacterium tuberculosis (EHB) are studied computationally, using the quantum mechanics/molecular mechanics (QM/MM) method. To do this, we modeled the alkylation and the hydrolysis steps of three substrates: trans-1,3-diphenylpropene oxide, trans-stilbene oxide and cis-stilbene oxide. Studying the regioselectivity for trans-1,3-diphenylpropene oxide, we determined that both enzymes prefer ring opening via attack on the benzylic carbon. In agreement with experimental studies, our computations show that the rate-limiting step is hydrolysis of the ester intermediate, with reaction barriers of approximately 13 to 18 kcal/mol. Using the barrier energies of this rate-limiting step, the three epoxides were ranked in order of reactivity. Though the reactivity order was correctly predicted for sEH, the predicted order for EHB did not correspond to experimental observations. Next, the electrostatic contributions of individual residues on the barrier height of the rate-limiting step were also studied. This revealed several residues important for catalysis. The secondary tritium kinetic isotope effect for the alkylation step was determined using a cluster model for the active site of sEH. The calculated value was 1.27, suggesting a late transition state for the rate-limiting step. Finally, we analyzed the reactivity trends using reactivity indicators from conceptual density functional theory, allowing us to identify ease of electron transfer as the primary driving force for the reaction.},
  author       = {Rabi, Sandra and Patel, Anand HG and Burger, Steven K and Verstraelen, Toon and Ayers, Paul W},
  issn         = {1040-0400},
  journal      = {STRUCTURAL CHEMISTRY},
  keyword      = {Epoxide hydrolase mechanism,QM/MM,Tuberculosis antibiotics,sEH,Epoxide hydrolase B,SOLUBLE EPOXIDE HYDROLASE,MOLECULAR-ORBITAL METHODS,EXTENDED BASIS-SETS,VALENCE BASIS-SETS,MINIMUM POLARIZABILITY PRINCIPLES,NONTOTALLY SYMMETRIC VIBRATIONS,DENSITY-FUNCTIONAL-APPROACH,FRONTIER-ELECTRON THEORY,TRANSITION-STATE THEORY,CHEMICAL-REACTIVITY},
  language     = {eng},
  number       = {5},
  pages        = {1501--1511},
  title        = {Exploring the substrate selectivity of human sEH and M. tuberculosis EHB using QM/MM},
  url          = {http://dx.doi.org/10.1007/s11224-017-0982-3},
  volume       = {28},
  year         = {2017},
}

Chicago
Rabi, Sandra, Anand HG Patel, Steven K Burger, Toon Verstraelen, and Paul W Ayers. 2017. “Exploring the Substrate Selectivity of Human sEH and M. Tuberculosis EHB Using QM/MM.” Structural Chemistry 28 (5): 1501–1511.
APA
Rabi, S., Patel, A. H., Burger, S. K., Verstraelen, T., & Ayers, P. W. (2017). Exploring the substrate selectivity of human sEH and M. tuberculosis EHB using QM/MM. STRUCTURAL CHEMISTRY, 28(5), 1501–1511.
Vancouver
1.
Rabi S, Patel AH, Burger SK, Verstraelen T, Ayers PW. Exploring the substrate selectivity of human sEH and M. tuberculosis EHB using QM/MM. STRUCTURAL CHEMISTRY. 2017;28(5):1501–11.
MLA
Rabi, Sandra, Anand HG Patel, Steven K Burger, et al. “Exploring the Substrate Selectivity of Human sEH and M. Tuberculosis EHB Using QM/MM.” STRUCTURAL CHEMISTRY 28.5 (2017): 1501–1511. Print.