Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS) 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Sci Rep. 2018 May 21;8(1):7954. doi: 10.1038/s41598-018-26325-4.
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.
代谢物通过ω-3 双键（ω-3 氧化）在二十碳五烯酸（EPA）中的氧化产生，最近被鉴定为新型抗炎脂质介质。因此，负责这种代谢途径的加氧酶（s）特别令人感兴趣。我们对小鼠细胞色素 P450（CYP）同工型进行了全基因组筛选，以探索参与 EPA 的 ω-3 氧化的酶。结果，选择并鉴定了 5 种 CYP 同工型（小鼠 Cyp1a2、2c50、4a12a、4a12b 和 4f18），它们将 EPA 的 ω-3 环氧化生成 17,18-环氧二十碳四烯酸（17,18-EpETE）。每个 CYP 同工型均确认了 17,18-EpETE 的立体选择性产生，分子建模表明手性差异源于各自 CYP 酶催化结构域中 EPA 结合构象的不同。
