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 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.
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, Japan. ab_rajjak@yahoo.co.in
Abdul Rajjak
AR
Shaikh
Riadh
R
Sahnoun
Ewa
E
Broclawik
Michihisa
M
Koyama
Hideyuki
H
Tsuboi
Nozomu
N
Hatakeyama
Akira
A
Endou
Hiromitsu
H
Takaba
Momoji
M
Kubo
Carlos A
CA
Del Carpio
Akira
A
Miyamoto
D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011789:Quantum Theory
D009025:Morpholines; C037574:morpholine; D003577:Cytochrome P-450 Enzyme System