Philipp Lachenmann: DELPHI Rationale


Habilitation Prize 1999

PD Dr. Gerhild van Echten Deckert

Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn

Glycosphingolipids: from metabolism to signal transduction

Glycosphingolipids are amphiphatic molecules consisting of a ceramide lipid moiety, embedded in the outer leaflet of the plasma membrane, linked to one of hundreds of different externally oriented oligosaccharide structures. They form cell type specific profiles which characteristically change in development, differentiation and oncogenic transformation, suggesting their implication in fundamental cellular processes including growth, differentiation, morphogenesis, cell to matrix interaction and cell to cell communication. Glycosphingolipids are believed to be integral components of the plasma membrane microdomains, known as rafts and caveolae. Furthermore, their biosynthesis has been shown to have a vital role for embryogenesis of mammals.

In the last decade sphingolipid metabolites were recognized as bioactive molecules; whereas sphingosine and sphingosine-1-phosphate were found to be primarily mitogenic signals, ceramide appears to provide the breaks for unrestrained cell growth, being involved in apoptosis, differentiation and senescence. For a better understanding of the relations between sphingolipid metabolism and intracellular signaling we analyzed the identity, intracellular localization and topology as well as the regulation of individual biosynthetic steps. Our work contributed substantially to the now accepted model for the biosynthesis of complex gangliosides. We also identified the potential key enzyme for the biosynthesis of ceramide, the dihydroceramide-desaturase. We are currently working on the isolation, characterization and regulation of this enzyme.

Experiments with synthetic sphingolipid analogs resulted in two interesting compounds which turned out to be valuable tools for studies of both: the regulation of sphingolipid biosynthesis and the role of sphingolipid metabolites in cell signaling. i.) 1-Methylthiodihydroceramide, a metabolically stable dihydroceramide analog uncouples de novo sphingolipid biosynthesis, by up-regulating sphinganine-kinase and thus depleting the cells of sphinganine, a vital biosynthetic precursor. We now investigate the mechanism of this regulatory process. ii.) cis-4- Methylsphingosine is a membrane permeable prodrug which is phosphorylated by the cells to cis-4- methylsphingosine-1-phosphate, a metabolically stable mimetic of the short living signaling molecule sphingosine-1-phosphate. Like the latter, it triggers cell proliferation and mobilization of intracellular calcium in quiescent Swiss 3T3 cells. cis-4- Methylsphingosine is, however, apoptotic in postmitotic neurons as well as in neuroblastoma cells. We now investigate the intracellular targets of this bioactive molecule as well as the cell type specific cascade of signal transduction.



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