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

研究成果: Article査読

抄録

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.

本文言語English
論文番号10119
ジャーナルInternational journal of molecular sciences
22
18
DOI
出版ステータスPublished - 2021 9

ASJC Scopus subject areas

  • 触媒
  • 分子生物学
  • 分光学
  • コンピュータ サイエンスの応用
  • 物理化学および理論化学
  • 有機化学
  • 無機化学

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