title: 17-OxoDHA Is a PPARα/γ Dual Covalent Modifier and Agonist.
abstract: 17-Hydroxy docosahexaenoic acid (17-HDHA) is an oxidized form of docosahexaenoic acid (DHA) and known as a specialized proresolving mediator. We found that a further oxidized product, 17-oxodocosahexaenoic acid (17-oxoDHA), activates peroxisome proliferator-activated receptors γ (PPARγ) and PPARα in transcriptional assays and thus can be classified as an α/γ dual agonist. ESI mass spectroscopy and X-ray crystallographic analysis showed that 17-oxoDHA binds to PPARγ and PPARα covalently, making 17-oxoDHA the first of a novel class of PPAR agonists, the PPARα/γ dual covalent agonist. Furthermore, the covalent binding sites were identified as Cys285 for PPARγ and Cys275 for PPARα.
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Egawa
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D018360:Crystallography, X-Ray; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists / Q000187:drug effects*; D017354:Point Mutation; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D047493:PPAR alpha; D047495:PPAR gamma; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid