Comprehensive analysis of the mouse cytochrome P450 family responsible for omega-3 epoxidation of eicosapentaenoic acid

  • Sci Rep. 2018 May 21;8(1):7954. doi: 10.1038/s41598-018-26325-4.
Yosuke Isobe  1  2 ,  Mai Itagaki  3  4 ,  Yuko Ito  4  5 ,  Satoko Naoe  3 ,  Kotoe Kojima  3  4 ,  Mitsunori Ikeguchi  4 ,  Makoto Arita  6  7  8
Affiliations
  • 1. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS) 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. [email protected].
  • 2. Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. [email protected].
  • 3. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS) 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
  • 4. Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
  • 5. Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
  • 6. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS) 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. [email protected].
  • 7. Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. [email protected].
  • 8. Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-0011, Japan. [email protected].
PMID: 29784972 DOI: 10.1038/s41598-018-26325-4
Abstract

Metabolites generated via oxygenation of the omega-3 double bond (omega-3 oxygenation) in eicosapentaenoic acid (EPA) have recently been identified as novel anti-inflammatory lipid mediators. Therefore, oxygenase(s) responsible for this metabolic pathway are of particular interest. We performed genome-wide screening of mouse Cytochrome P450 (CYP) isoforms to explore Enzymes involved in omega-3 oxygenation of EPA. As a result, 5 CYP isoforms (mouse CYP1A2, 2c50, 4a12a, 4a12b, and 4f18) were selected and identified to confer omega-3 epoxidation of EPA to yield 17,18-epoxyeicosatetraenoic acid (17,18-EpETE). Stereoselective production of 17,18-EpETE by each CYP isoform was confirmed, and molecular modeling indicated that chiral differences stem from different EPA binding conformations in the catalytic domains of respective CYP Enzymes.

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