Carcinogenic Metabolic Activation Process of Naphthalene by the Cytochrome P450 Enzyme 1B1: A Computational Study

Abstract

The metabolic activation and transformation of naphthalene by the cytochrome P450 enzyme (CYP 1B1) plays an important role in its potential carcinogenicity. The process has been explored by a quantum mechanics/molecular mechanics (QM/MM) computational method. Molecular dynamic simulations were performed to explore the interaction between naphthalene and CYP 1B1. Naphthalene involves αand β-carbon, the electrophilic addition of which would result in different reaction pathways. Our computational results show that both additions on αand βcarbon can generate naphthalene 1,2-oxide. The activation barrier for the addition on βcarbon is higher than that for the α-carbon by 2.6 kcal•mol −1 , which is possibly caused by the proximity between β-carbon and the iron-oxo group of Cpd I in the system. We also found that naphthalene 1,2-oxide is unstable and the O−C bond cleavage easily occurs via cellular hydronium ion, hydroxyl radical/anion; then it will convert to the potential ultimate carcinogen 1,2-naphthoquinone. The results demonstrate and inform a detailed process of generating naphthalene 1,2-oxide and new predictions for its conversion.

Multiscale Simulations on the Catalytic Plasticity of CYP76AH1

“…Sugiol can be obtained directly from ferruginol, and the formation of 11-hydroxy-ferruginol in this manner is prohibited. In contrast, according to recent studies on the mechanism of 1,2-naphalenediol production from naphthalene, 11-hydroxy-ferruginol may be obtained directly from abietatriene by epoxidation ( Bao et al, 2019 ). Therefore, DFT calculations were performed to probe the reactivity of abietatriene in wild-type and mutant systems based on the truncated protein–ligand structure validated in the aforementioned MD simulations.…”

“…Finally, regarding the generation of C11-hydroxy products in the mutant enzyme, the reaction pathway from ferruginol was ruled out since ferruginol maintains an unfavorable attack distance (greater than 7 Å, i.e., fer-C11 binding pose), as shown in Figure 7 . Here, we refer to a previously established reaction mechanism ( Bao et al, 2019 ) that naphthalene can be converted to 1,2-naphalenediol, a double ortho-hydroxy product similar to 11-hydroxyl ferruginol, via epoxidation and then opening by OH radicals and water molecules (see Supplementary Figure S8 for details). Since a reactive C12-near-attack binding pose of abietatriene was detected in our MD simulations (provided in Figure 7 ), we propose that oxygen will attack C11 to form the epoxidation product (mut-IM2).…”

“…As shown in Figure 8B , DFT calculations show that this process is very facile with a low activation barrier (10.1 kcal/mol) and heat release (2 kcal/mol). Then mut-IM2 can be converted to the final product 11-hydroxy-ferruginol via a ring-opening reaction according to a previous study ( Bao et al, 2019 ), as shown in Figure 8B , Supplementary Figure S8 .…”

Embedding Methods for Quantum Chemistry: Applications from Materials to Life Sciences

“…Transition state for an epoxidation reaction with cytochrome P450 enzyme 1B1 at a 10 ns snapshot, calculated at the QM:MM level. Adapted with permission from ref .…”

“…Enzymatic reaction mechanisms can be readily computed with QM for the active sites and MM for the remaining fragment of an enzyme. Bao et al 125 have studied the metabolic processes of Cytochrome P450 enzyme on the activation of polycyclic aromatic hydrocarbons (PAHs) such as naphthalene to naphthalene oxide (Figure 7). The study of PAHs is important due to their environmental 126 and carcinogenic 127 concerns and as activated by P450 enzymes in the body.…”