Limonoids, a novel type of inhibitors of sphingomyelin biosynthesis to study the membrane dynamics of sphingolipid domains

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25460081
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: FHULL IN・MATSUDA 独立行政法人理化学研究所, 小林脂質生物学研究室, 客員研究員 (30469928)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: sphingolipids / sphingomyelin / ceramide / cancer / infection / lipid domains / transbilayer movements / lipid dynamics

Outline of Annual Research Achievements

Sphingolipids are important cell components for the formation of membrane lipid bilayers as well as for cell growth, apoptosis and inflammation. Using a selective high-throughput microscopy-based screening, we recently isolated natural compounds, Limonoids as new inhibitor type of the biosynthesis of sphingomyelin, the major sphingolipid in eukaryotic membranes. In order to precise their therapeutic properties, we set up the experimental conditions to analyze their effects on various sphingolipid-dependent events: 1) modulation of sphingolipid content by limonoid Gedunin pretreatment improved the efficiency of some anticancer drugs (doxorubicin but not Paclitaxel) in HeLa cells; 2) sphingolipid-dependent growth of Plasmodium malaria parasite in erythrocytes and Toxoplasma parasite in HeLa cells was decreased by limonoid Gedunin pretreatment of the cells but had a toxic effect by itself; 3) since Limonoids favored the formation of ceramide-rich domains in the membrane, we tried to analyse the ceramide transbilayer movement in vitro in unilamellar vesicles with new type of sulhydryl analogs of ceramides; 4) the membrane distribution of sphingomyelin is important to control various events as diacylglycerol transbilayer movement .

Research Products

• [Journal Article] Visualization of the heterogeneous distribution of sphingomyelin associated with cytokinesis, cell polarity and sphingolipidosis (2015)
  • Author(s): Makino A, Abe M, Murate M, Inaba T, Yilmaz N, Hullin-Matsuda F, Kishimoto T, Schieber NL, Taguchi T, Arai H, Anderluh G, Parton RG, Kobayashi T.
  • Journal Title: FASEB J Volume: 29 Pages: 477-493
  • DOI: 10.1096/fj.13-247585
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of the transbilayer movement of diacylglycerol in the plasma membrane (2014)
  • Author(s): Ueda Y, Ishitsuka R, Hullin-Matsuda F, Kobayashi T.
  • Journal Title: Biochimie Volume: 107 Pages: 43-50
  • DOI: 10.1016/j.biochi.2014.09.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lipid compartmentalization in the endosome system (2014)
  • Author(s): Hullin-Matsuda F, Taguchi T, Greimel P, Kobayashi T.
  • Journal Title: Sem Cell Dev Biol Volume: 31 Pages: 48-56
  • DOI: 10.1016/j.semcdb.2014.04.010
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Cholesterol Trafficking for Steroid Biosynthesis in MA-10 Mouse Tumor Leydig Cells. (2015)
  • Author(s): agannathan S, Chebbi S, Hullin-Matsuda F, Kobayashi T and Papadopoulos V.
  • Organizer: American Society for Biochemistry and Molecular Biology
  • Place of Presentation: ボストン
  • Year and Date: 2015-03-28 – 2015-04-01