Quantum chemical studies for oxidation of morpholine by Cytochrome P450

Since morpholine oxidation has recently been shown to involve Cytochrome P450, the study on its mechanism at molecular level using quantum chemical calculations for the model of cytochrome active site is reported here. The reaction pathway is investigated for two electronic states, the doublet and t...

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Bibliographic Details
Published in:Journal of inorganic biochemistry 2009, Vol.103 (1), p.20-27
Main Authors: Shaikh, Abdul Rajjak, Sahnoun, Riadh, Broclawik, Ewa, Koyama, Michihisa, Tsuboi, Hideyuki, Hatakeyama, Nozomu, Endou, Akira, Takaba, Hiromitsu, Kubo, Momoji, Carpio, Carlos A.Del, Miyamoto, Akira
Format: Article
Language:English
Subjects:
Catalytic Domain
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
DFT modeling
Enzymatic oxidation
Morpholine biodegradation
Morpholines - chemistry
Morpholines - metabolism
Oxidation-Reduction
Quantum Theory
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Summary:Since morpholine oxidation has recently been shown to involve Cytochrome P450, the study on its mechanism at molecular level using quantum chemical calculations for the model of cytochrome active site is reported here. The reaction pathway is investigated for two electronic states, the doublet and the quartet, by means of density functional theory. The results show that morpholine hydroxylation occurs through hydrogen atom abstraction and rebound mechanism. However, in the low spin state, the reaction is concerted and hydrogen atom abstraction yields directly ferric-hydroxy morpholine complex without a distinct rebound step while in quartet state the reaction is stepwise. The presence of nitrogen in a morpholine heterocycle is postulated to greatly facilitate hydrogen abstraction. The hydroxylated product undergoes intramolecular hydrogen atom transfer from hydroxy group to nitrogen, leading to the cleavage of the C–N bond and the formation of 2-(2-aminoethoxy) acetaldehyde. The cleavage of the C–N bond is indicated as the rate-determining step for the studied reaction. The assistance of explicit water molecule is shown to lower the energy barrier for the C–N bond cleavage in enzymatic environment whereas solvent effects mimicked by COSMO solvent model have minor influence on relative energies along the pathway.
ISSN:0162-0134
1873-3344
DOI:10.1016/j.jinorgbio.2008.08.013