Egawa Daichi, Itoh Toshimasa, Akiyama Yui, Saito Tomoko, Yamamoto Keiko
Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
ACS Chem Biol. 2016 Sep 16;11(9):2447-55. doi: 10.1021/acschembio.6b00338. Epub 2016 Jul 1.
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.
17-羟基二十二碳六烯酸（17-HDHA）是二十二碳六烯酸（DHA）的一种氧化形式，被认为是一种特殊的促消退介质。我们发现，一种进一步氧化的产物，17-氧代二十二碳六烯酸（17-oxoDHA），在转录分析中可激活过氧化物酶体增殖物激活受体γ（PPARγ）和PPARα，因此可被归类为α/γ双重激动剂。电喷雾电离质谱（ESI）和X射线晶体学分析表明，17-oxoDHA与PPARγ和PPARα共价结合，使17-oxoDHA成为一类新型PPAR激动剂中的首个成员，即PPARα/γ双重共价激动剂。此外，共价结合位点被确定为PPARγ的Cys285和PPARα的Cys275。
