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

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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 9.3kcal/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 l -methylxanthine by intramolecular rearrangement.

Original languageEnglish
Pages (from-to)730-734
Number of pages5
JournalMaterials Transactions
Volume48
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

All Science Journal Classification (ASJC) codes

  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanics of Materials
  • Mechanical Engineering

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    Ismael, M., Del Carpio, C. A., Shaikh, A. R., Tsuboi, H., Koyama, M., Hatakeyama, N., Endou, A., Takaba, H., Kubo, M., Broclawik, E., & Miyamoto, A. (2007). A DFT study of the heme role in the N-demethylation of theophylline mediated by compound i of cytochrome P450. Materials Transactions, 48(4), 730-734. https://doi.org/10.2320/matertrans.48.730