A DFT Study of the Heme Role in the N-Demethylation of Theophylline Mediated by Compound I of Cytochrome P450

Mohamed Ismael; Carlos A. Del Carpio; Abdul Rajjak Shaikh; Hideyuki Tsuboi; Michihisa Koyama; Nozomu Hatakeyama; Akira Endou; Hiromitsu Takaba; Momoji Kubo; Ewa Broclawik; Akira Miyamoto

doi:10.2320/matertrans.48.730

Mohamed Ismael, Carlos A. Del Carpio, Abdul Rajjak Shaikh, Hideyuki Tsuboi, Michihisa Koyama, Nozomu Hatakeyama, Akira Endou, Hiromitsu Takaba, Momoji Kubo, Ewa Broclawik, Akira Miyamoto

Author information

Mohamed Ismael
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Carlos A. Del Carpio
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Abdul Rajjak Shaikh
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Hideyuki Tsuboi
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Michihisa Koyama
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Nozomu Hatakeyama
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Akira Endou
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Hiromitsu Takaba
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
Momoji Kubo
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
PRESTO, Japan Science and Technology Agency
Ewa Broclawik
Institute of Catalysis, Polish Academy of Sciences
Akira Miyamoto
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University
New Industry Creation Hatchery Center, Tohoku University

Keywords: Theophylline, single electron transfer mechanism, Hydrogen atom transfer mechanism, CYP1A2, compound I, metabolism

JOURNAL FREE ACCESS

2007 Volume 48 Issue 4 Pages 730-734

DOI https://doi.org/10.2320/matertrans.48.730

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Abstract

Using accurate DFT calculations we have examined the role that Compound I of cytochrome P450 plays as a catalyst in the conversion of theophylline to 1-methylxanthine. This reaction proceeds in two steps according to the characteristics of the oxygen rebound mechanism. In this study we found that the activation energy for the transition state corresponding to the abstraction of the H atom at the C13 in theophylline is 9.3 kcal/mol. This H atom abstraction is the rate-determining step in this reaction which takes place via a single electron transfer (SET) mechanism and leads to an intermediate containing theophylline cationic and iron-hydroxo species. The rebounding step between the reaction intermediate and the product alcohol complex is a barrierless step. The alcohol complex is then separated from the heme moiety and yields 1-methylxanthine by intramolecular rearrangement.

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