English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Mechanistic Insights into the Directing Effect of Thr303 in Ethanol Oxidation by Cytochrome P450 2E1

Lu, Q., Song, J., Wu, P., Li, C., & Thiel, W. (2019). Mechanistic Insights into the Directing Effect of Thr303 in Ethanol Oxidation by Cytochrome P450 2E1. ACS Catalysis, 9(6), 4892-4901. doi:10.1021/acscatal.9b00907.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files
hide Files
:
cs9b00907_si_001_pub 630.pdf (Supplementary material), 873KB
Name:
cs9b00907_si_001_pub 630.pdf
Description:
Supporting Information
OA-Status:
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Lu, Qianqian1, 2, Author
Song, Jinshuai1, 2, Author
Wu, Peng1, 3, Author
Li, Chunsen1, 2, Author
Thiel, Walter4, Author           
Affiliations:
1State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China, ou_persistent22              
2Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen, Fujian 361005, China, ou_persistent22              
3University of Chinese Academy of Sciences, Beijing 100049, China, ou_persistent22              
4Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              

Content

show
hide
Free keywords: P450; alcohol oxidation; hydrogen abstraction; quantum mechanics/molecular mechanics; molecular dynamics
 Abstract: There is a long-standing mechanistic consensus that alcohol oxidation by cytochrome P450 enzymes is triggered by hydrogen abstraction from the α-C–H bond of the alcohol. Through combined molecular dynamics simulations and quantum mechanics/molecular mechanics calculations we demonstrate that this is not the case in P450 2E1-mediated ethanol oxidation. We show that while the O–H bond is stronger than the α-C–H bonds in alcohols, the intrinsic reactivity of O–H and α-C–H bonds is comparable for hydrogen abstraction, due to the strong electrostatic interaction between the ethanol hydroxyl group and the Fe═O moiety. Thus, the binding of ethanol to the Fe═O moiety in the P450 2E1 pocket is of particular importance to the reaction mechanism. We further show that the Thr303 residue plays a crucial role in confining the ethanol substrate in the active site of P450 2E1 and thereby steering the initial hydrogen abstraction from the O–H bond of ethanol. Because of the highly endothermic O–H bond cleavage, the subsequent hydrogen abstraction of α-C–H bond is the overall rate-determining step for ethanol oxidation. These mechanistic findings are in agreement with available experimental data (e.g., kinetic isotope experiments and electron spin resonance analysis). Our work sheds light on the puzzling mechanism of ethanol oxidation in P450 2E1 by identifying the directing effect of Thr303 on substrate orientation, which complements its role as a proton-shuttle mediator during the formation of Compound I.

Details

show
hide
Language(s): eng - English
 Dates: 2019-03-012019-04-182019-06-07
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acscatal.9b00907
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: ACS Catalysis
  Abbreviation : ACS Catal.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Washington, DC : ACS
Pages: - Volume / Issue: 9 (6) Sequence Number: - Start / End Page: 4892 - 4901 Identifier: ISSN: 2155-5435
CoNE: https://pure.mpg.de/cone/journals/resource/2155-5435