17-OxoDHA Is a PPARα/γ Dual Covalent Modifier and Agonist

  • ACS Chem Biol. 2016 Sep 16;11(9):2447-55. doi: 10.1021/acschembio.6b00338.
Daichi Egawa  1 ,  Toshimasa Itoh  1 ,  Yui Akiyama  1 ,  Tomoko Saito  1 ,  Keiko Yamamoto  1
Affiliations
  • 1. Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
PMID: 27337155 DOI: 10.1021/acschembio.6b00338
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.

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