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.
Highlights
Dietary omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert a wide range of beneficial effects on human health[1,2,3]
There are no comprehensive studies to evaluate the PUFA-metabolizing activity of cytochrome P450 (CYP) enzymes
We investigated the formation of epoxidized and hydroxylated regioisomers of arachidonic acid (AA), EPA, and DHA by candidate CYPs as well as the stereoselectivity of omega-3 epoxide of EPA
Summary
Dietary omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert a wide range of beneficial effects on human health[1,2,3]. E-series resolvins are lipid mediators derived from EPA that actively dampen inflammation to maintain tissue homeostasis[7,8,9,10,11] They are biosynthesized through several lipoxygenase pathways from a common precursor, 18-hydroxyeicosapentaenoic acid (18-HEPE). 17,18-EpETE induces relaxation in human pulmonary artery and airway smooth muscles through the activation of calcium-activated potassium (BK) channels that reduce calcium sensitivity of the contractile apparatus[15] Both 18-HEPE and 17,18-EpETE are generated from EPA through oxygenation of the omega-3 double bond, which distinguishes EPA from omega-6 AA. Recent studies have shown that omega-3 PUFAs can be metabolized by CYP enzymes into a series of oxygenated metabolites[19,20,21,22,23,24,25,26,27]. To rationalize the observed stereoselectivity of EPA oxygenation by CYPs, molecular modeling of CYP–EPA interaction was performed
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