1-Methylthiodihydroceramide, a novel analog of dihydroceramide, stimulates sphinganine degradation resulting in decreased de novo sphingolipid biosynthesis.

The Journal of Biological Chemistry
G van Echten-DeckertK Sandhoff

Abstract

1-Methylthiodihydroceramide (10 microM) decreased de novo ceramide biosynthesis by about 90% in primary cultured cerebellar neurons. Accordingly, de novo formation of sphingomyelin and of glycosphingolipids, all of which contain ceramide in their backbone, was reduced in a time- and concentration-dependent manner by up to 80%. Complex sphingolipid synthesis was restored upon addition of dihydroceramide or ceramide, in micromolar concentrations, to the culture medium, suggesting that none of the glycosyltransferases involved in glycosphingolipid biosynthesis is inhibited by this analog. Assays of the enzymes catalyzing sphinganine biosynthesis, as well as its N-acylation to form dihydroceramide, revealed that they were also not affected. In contrast, there was a 2.5-fold increase in the activity of sphinganine kinase. Reduction of de novo sphingolipid biosynthesis by 1-methylthiodihydroceramide is therefore due to its ability to deplete cells of newly formed free sphinganine. As a consequence of depletion of sphinganine levels, 1-methylthiodihydroceramide disrupted axonal growth in cultured hippocampal neurons in a manner similar to that reported for direct inhibitors of sphingolipid synthesis; thus, there was essentially no axo...Continue Reading

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Citations

Jun 5, 2003·Biochimica Et Biophysica Acta·Kentaro Hanada
Jul 9, 1999·Biochimica Et Biophysica Acta·R GhidoniA Giuliani
Mar 9, 1999·Alcoholism, Clinical and Experimental Research·A SlomianyB L Slomiany
Jan 26, 2007·ChemMedChem·Antonio DelgadoGemma Fabriás
Jul 18, 2006·Biochimica Et Biophysica Acta·Gerhild van Echten-Deckert, Thomas Herget
Oct 7, 2014·Biochimica Et Biophysica Acta·S Rodriguez-CuencaA Vidal-Puig
Jun 5, 2003·Journal of Lipid Research·Mihaela DragusinGerhild van Echten-Deckert
May 11, 2004·Arteriosclerosis, Thrombosis, and Vascular Biology·Tilla S WorgallRichard J Deckelbaum
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