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J. Biol. Chem., Vol. 280, Issue 14, 14145-14153, April 8, 2005

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,-Unsaturated Ketone Is a Core Moiety of Natural Ligands for Covalent Binding to Peroxisome Proliferator-activated Receptor ^*

Takuma Shiraki, Narutoshi Kamiya¶, Sayaka Shiki, Takashi S. Kodama||**, Akira Kakizuka, and Hisato Jingami

From the Departments of Molecular Biology, ^¶Computational Biology, and ^||Structural Biology, Biomolecular Engineering Research Institute, 6-2-3 Furuedai, Suita-City, Osaka 565-0874, ^**Japan Biological Information Research Institute Center, Japan Biological Informatics Consortium, 2-41-6 Aomi, Koto-Ku, Tokyo 135-0064, Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Sakyo-Ku, Kyoto 606-8501, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan

Peroxisome proliferator-activated receptor (PPAR) functions in various biological processes, including macrophage and adipocyte differentiation. Several natural lipid metabolites have been shown to activate PPAR. Here, we report that some PPAR ligands, including 15-deoxy-^12,14-prostaglandin J₂, covalently bind to a cysteine residue in the PPAR ligand binding pocket through a Michael addition reaction by an ,-unsaturated ketone. Using rhodamine-maleimide as well as mass spectroscopy, we showed that the binding of these ligands is covalent and irreversible. Consistently, mutation at the cysteine residue abolished abilities of these ligands to activate PPAR, but not of BRL49653 a non-covalent synthetic agonist, indicating that covalent binding of the ,-unsaturated ketone in the natural ligands was required for their transcriptional activities. Screening of lipid metabolites containing the ,-unsaturated ketone revealed that several other oxidized metabolites of hydroxyeicosatetraenoic acid, hydroxyeicosadecaenoic acid, and prostaglandins can also function as novel covalent ligands for PPAR. We propose that PPAR senses oxidation of fatty acids by recognizing such an ,-unsaturated ketone as a common moiety.

Received for publication, January 25, 2005 , and in revised form, February 4, 2005.

^* This work was supported by a research grant endorsed by the New Energy and Industrial Technology Development Organization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 81-6-6872-8214; Fax: 81-6-6872-8210; E-mail: jingami{at}beri.or.jp.

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