Deciphering Structural Alterations Associated with Activity Reductions of Genetic Polymorphisms in Cytochrome P450 2A6 Using Molecular Dynamics Simulations.

Koichi Kato,Rika Nokura,Masahiro Hiratsuka,Yoshinobu Ishikawa,Hiroki Hosono,Eiji Kurimoto,Tomoki Nakayoshi,Akifumi Oda

doi:10.3390/ijms221810119

Abstract

Cytochrome P450 (CYP) 2A6 is a monooxygenase involved in the metabolism of various endogenous and exogenous chemicals, such as nicotine and therapeutic drugs. The genetic polymorphisms in CYP2A6 are a cause of individual variation in smoking behavior and drug toxicities. The enzymatic activities of the allelic variants of CYP2A6 were analyzed in previous studies. However, the three-dimensional structures of the mutants were not investigated, and the mechanisms underlying activity reduction remain unknown. In this study, to investigate the structural changes involved in the reduction in enzymatic activities, we performed molecular dynamics simulations for ten allelic mutants of CYP2A6. For the calculated wild type structure, no significant structural changes were observed in comparison with the experimental structure. On the other hand, the mutations affected the interaction with heme, substrates, and the redox partner. In CYP2A6.44, a structural change in the substrate access channel was also observed. Those structural effects could explain the alteration of enzymatic activity caused by the mutations. The results of simulations provide useful information regarding the relationship between genotype and phenotype.

Highlights

To investigate the structures of CYP2A6 mutants, the molecular dynamics (MD) simulations were performed, and the convergences were evaluated by Root mean square deviations (RMSDs) (Figure 2)
We performed the MD simulation for the wild type and 10 mutants and investigated the structural changes related to the reduction in enzymatic activity for the mutants of
In addition to drug metabolism, CYP2A6 was reported to be involved in hepatocellular carcinoma by contributing to immune regulation [14]

Summary

Introduction

Cytochrome P450 (CYP) is a monooxygenase that plays a central role in the synthesis pathways of steroids, fatty acids, lipid-soluble vitamins, and eicosanoids [1]. CYP is a primary enzyme for drug metabolism [2,3,4]. The active site of CYP includes an heme iron that mediates electron transfer related to oxidation reactions [5,6]. Drug metabolism by CYP proceeds via oxidation, reduction (phase I), hydrolysis, and conjugation (phase II). The phase I oxidation requires electron carriers such as nicotinamide adenine

Methods

Results

Conclusion