Medicinal Chemistry

Insight into the Mutation-Induced Decrease of the Enzymatic Activity of Human Cytochrome P450 1A2

Abstract

Bei-Li Ying, Bo-Tao Fa, Shan Cong, Yang Zhong and Jing-Fang Wang

As an important member of CYP1 sub-family, CYP1A2 mediates the metabolisms of approximately 5-10% of the currently clinical medicines, and plays a predominant role in the activation of precarcinogens. F186L mutation in this CYP enzyme is found to have ability to reduce the enzymatic activity. As this mutation is far away from the active site and has no influence on the protein expression, the detailed mechanism for F186L-induced the decrease of the enzymatic activity of CYP1A2 is still unknown. In the current study, we employed molecular dynamics simulation and free energy calculation to study the wild-type and F186L mutant CYP1A2 with a α-naphthoflavone (ANF) bound in the active site. Our simulations showed that instead of changing the backbone structure, the F186L mutation has significant impact on the side-chain conformations, resulting in a smaller active site and larger solvent accessible surface. The former could weaken the binding affinity of ANF in the active site, making the substrate far away from the active site so as to reduce the enzymatic activity. The latter could keep the substrate access channel in a closed state in most case, which was not propitious for the substrate entering into the active site by the substrate access channel. Our findings can reveal an in-depth understanding for the mechanism of the mutation-induced decrease of the enzymatic activity of human CYP1A2, providing useful information on the structure-function relationships of human CYP enzymes.