| Budget Amount *help |
¥3,980,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Sphingolipids are regarded as lipid secondary messengers in mammalian cells and cell membranes, and are now accepted to play an important role in signal transduction and molecular recognition processes in cell membranes. Among them, sphingomyelin (SM) is known as a major component to form a raft domain, which is the lipid microdomain consisting of SM and cholesterol as major components. Generally, this particular domain is considered to play a key role in processes such as membrane trafficking and signal transduction. However, the distinct role of SM to construct the raft domain has not been understood. We established a stereocontrolled versatile method for the synthesis of various kinds of natural sphingolipids, such as sphingosine, ceramide, sphingosine 1-phosphate, sphingomyelin, and functionalized sphingosine derivatives by two types of combinations of the olefin cross metathesis reaction. One was between 1-pentadecene as an olefin part and the amino alcohol part, which were prepared starting from L-serine through 1-silyloxy-2-amino-4-penten-3-ol resulting from the stereoselective reduction, and the other was between fluorescence labeled olefin parts and the same amino alcohol part. We synthesized four types of SM analogues, in which the phosphate oxygen connecting the phosphocholine head group to the sphingosine backbone was replaced with CH_2, NH, Nme, and S groups. In addition, fluorescence-labeled sphingomyelin methylene analogue was also synthesized by the same method using the fluorescence-labeled olefin. The molecular properties and membrane behavior of the synthesized CH2, NH, and S sphingomyelin analogues of SM were examined comparing with natural palmitoyl SM (PSM), by Slotte's group of Abo Academi University in Finland. It was suggested from the obtained data that the properties of the bond linking the phosphocholine head group to the 1-hydroxy group on the ceramide molecule is important for the stability of SM/SM and SM/cholesterol interactions.
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