A theoretical study on the mechanism of a superficial mutation inhibiting the enzymatic activity of CYP1A2.

CYP1A2, one of the major members of cytochrome P450 in human liver, participates in the metabolism of various drugs. While most harmful mutations are located near the catalytic core of CYP1A2, a recently found loss-of-function mutation, F186L, is on the surface. By far, function of this superficial residue remains unclear. In this paper, 7-ethoxyresorufin, a widely used agent in benchmarking the O-deethylation activities of CYP1A subfamily enzymes, was employed as a substrate to investigate the impact of the F186L mutation through ensemble docking and molecular dynamics simulations. It was found that the F186L mutation altered the binding inclination of the substrate through a series of changes on the catalytic pocket, which are, actually, long-range effects. The activities of access channels in the enzyme are also affected by the F186L mutation and the substrate binding. Based on these findings, a detailed mechanism of how F186 regulates the functions of CYP1A2 was proposed, and it may shed light on the diverse effects of SNPs and the personalized drug design.