Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Lipid Res. 2014 May 21;55(7):1386-1396. [Epub ahead of print]

Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2.

Author information

  • 1Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan Department of Respiratory Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 2Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
  • 3Open Innovation Center for Drug Discovery, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 4Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 5Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 6Department of Respiratory Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 7Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

LPCAT2 inhibitor; N-phenylmaleimide derivatives; TSI-01; fluorescent probe; high-throughput screening; inflammation; lipid mediator; lyso-PAF acetyltransferase; lysophospholipid acyltransferase; platelet-activating factor

PMID:
24850807
[PubMed - as supplied by publisher]
PMCID:
PMC4076079
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk