An epoxidation mechanism of carbamazepine by CYP3A4

Abstract

Human CYP3A4 catalyzes the 10,11-epoxidation of carbamazepine (CBZ). However, the epoxide is less stable in terms of potential energy than hydroxides of the six-membered aromatic ring. To clarify the reason why CYP3A4 produces such an energetically unfavorable compound, the mechanism of epoxidation of CBZ by CYP3A4 was investigated by theoretical calculations. The reaction consisted of two elementary processes in which two C-O bonds were generated stepwise. The rate-determining step was the first one and the activation energy was 21.3kcal/mol at the DFT (B3LYP/6-31G( * *)) level. The activation energy level of the first step of the 10,11-epoxidation was lower than that of the hydroxylation of the aromatic ring. For this reason, 10,11-epoxidation is more probable than hydroxylation of the aromatic ring, and only 10,11-epoxide is formed.

Molecular modeling study on orphan human protein CYP4A22 for identification of potential ligand binding site

“…5B), and interacts with AA (Table 1). In the CYP3A4 carbamazepine epoxidation mechanism, F304 and A305 were located at the nearest position to the Fe atom and it is noted that they hold the substrate near the heme Fe atom for the reaction [40]. E321 of CYP4A22 is corresponding to A305 in CYP3A4.…”

Molecular dynamics and density functional studies on the metabolic selectivity of antipsychotic thioridazine by cytochrome P450 2D6: Connection with crystallographic and metabolic results

“…In contrast, theoretical computations can reveal metabolic mechanisms at the atomic and electronic levels. [19][20][21][22][23][24] In fact, Hoshino et al 20,23 demonstrated that molecular dynamics (MD) and density functional theory (DFT) calculations can 4 play a significant and indispensable role in the detailed understanding of CYP3A4-mediated metabolism of carbamazepine.…”

High warfarin sensitivity in carriers of CYP2C9*35 is determined by the impaired interaction with P450 oxidoreductase

“…However, the recent advances in resolution of three-dimensional structures of many CYPs including CYP2C9 13,14 allowed the development of various computational approaches that are currently applied for quantitative prediction of pharmacokinetics, interaction between the enzyme and its substrates, and also redox partners. [15][16][17][18][19] Thus, molecular dynamic simulations and subsequent substrate-docking simulations have been performed to clarify the mechanisms of enzymatic activity decrease in the different allelic variants of CYP2C9. 20 Amino-acid substitutions in these proteins were found to increase the fluctuation of the residues responsible for the substrate holding and alteration of the substrate-binding pocket.…”