Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2 |
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Authors: | Megumi Tarui Hideo Shindou Kazuo Kumagai Ryo Morimoto Takeshi Harayama Tomomi Hashidate Hirotatsu Kojima Takayoshi Okabe Tetsuo Nagano Takahide Nagase Takao Shimizu |
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Institution: | 2. Department of Respiratory Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;11. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;4. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan |
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Abstract: | Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid mediator. In response to extracellular stimuli, PAF is rapidly biosynthesized by lyso-PAF acetyltransferase (lyso-PAFAT). Previously, we identified two types of lyso-PAFATs: lysophosphatidylcholine acyltransferase (LPCAT)1, mostly expressed in the lungs where it produces PAF and dipalmitoyl-phosphatidylcholine essential for respiration, and LPCAT2, which biosynthesizes PAF and phosphatidylcholine (PC) in the inflammatory cells. Under inflammatory conditions, LPCAT2, but not LPCAT1, is activated and upregulated to produce PAF. Thus, it is important to develop inhibitors specific for LPCAT2 in order to ameliorate PAF-related inflammatory diseases. Here, we report the first identification of LPCAT2-specific inhibitors, N-phenylmaleimide derivatives, selected from a 174,000-compound library using fluorescence-based high-throughput screening followed by the evaluation of the effects on LPCAT1 and LPCAT2 activities, cell viability, and cellular PAF production. Selected compounds competed with acetyl-CoA for the inhibition of LPCAT2 lyso-PAFAT activity and suppressed PAF biosynthesis in mouse peritoneal macrophages stimulated with a calcium ionophore. These compounds had low inhibitory effects on LPCAT1 activity, indicating that adverse effects on respiratory functions may be avoided. The identified compounds and their derivatives will contribute to the development of novel drugs for PAF-related diseases and facilitate the analysis of LPCAT2 functions in phospholipid metabolism in vivo. |
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Keywords: | TSI-01 LPCAT2 inhibitor N-phenylmaleimide derivatives platelet-activating factor high-throughput screening lyso-PAF acetyltransferase lipid mediator inflammation fluorescent probe lysophospholipid acyltransferase |
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