Theoretical study of the mechanism of acetaldehyde hydroxylation by compound I of CYP2E1.
Recent experimental studies revealed that cytochrome P450 2E1 (CYP2E1) could metabolize not only ethanol but also its primary product, acetaldehyde, accompanying the well-known acetaldehyde dehydrogenases (ALDH) in the metabolism of acetaldehyde. Mechanistic aspects of acetaldehyde hydroxylation by Compound I model active species of CYP2E1 were investigated by means of B3LYP DFT calculations in the present paper. Our study results demonstrate that acetaldehyde hydroxylation by CYP2E1 is in accord with the effectively concerted mechanisms both on the high quartet spin state (HS) and on the low doublet spin state (LS). The rate-limiting step is H-abstraction, and the activation energy is about 11.7 approximately 14.0 kcal/mol on the quartet (doublet) reaction route, which is about one-half to one-third of that needed by methane hydroxylation. The phenomenon that the HS and LS reaction routes are both effectively concerted was shown for the first time to occur in trans-2-phenyl-iso-propylcyclopropane hydroxylation by Kumar et al. (see Figure 7 in the paper of Kumar, D.; de Visser, S. P.; Sharma, P. K.; Cohen, S.; Shaik, S. J. Am. Chem. Soc. 2004, 126, 1907) and was confirmed in our work of acetaldehyde hydroxylation by cytochrome P450. Theoretical exploration of the HS O-rebound barrier degradation is also presented in the present paper on the basis of Shaik's valence bond (VB) model.
State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People's Republic of China.
Yong
Y
Wang
Hongming
H
Wang
Yonghua
Y
Wang
Chuanlu
C
Yang
Ling
L
Yang
Keli
K
Han
D000079:Acetaldehyde / Q000737:chemistry*; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry*; D006900:Hydroxylation; D008962:Models, Theoretical
D019392:Cytochrome P-450 CYP2E1; D000079:Acetaldehyde