Deciphering structural alterations associated with activity reductions of genetic polymorphisms in cytochrome p450 2a6 using molecular dynamics simulations

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number10119
JournalInternational journal of molecular sciences
Volume22
Issue number18
DOIs
Publication statusPublished - 2021 Sep

Keywords

  • Cytochrome P450
  • Drug-metabolizing enzyme
  • Genetic polymorphism
  • Molecular dynamics simulation
  • Structural analysis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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