Abstract
Most mammalian sphingolipids contain a 4,5-(E)-double bond. We report on the chemical synthesis of a dihydroceramide derivative that prevents the introduction of the double bond into sphingolipids. Minimal alteration of the parent structure by formally replacing the hydrogen atoms in the 5- and in the 6-position of the sphinganine backbone by a methylene group leads to an inhibitor of dihydroceramide desaturase in cultured cells. In the presence of 10–50 μM of compound (1), levels of biosynthetically formed dihydroceramide and—surprisingly—also of phytoceramide are elevated at the expense of ceramide. The cells respond to the lack of unsaturated sphingolipids by an elevation of mRNAs of enzymes required for sphingosine formation. At the same time, the analysis of proliferation and differentiation markers indicates that the sphingolipid double bond is required to keep the cells in a differentiated state.
Highlights
Most mammalian sphingolipids contain an (E)-configured double bond between the carbon atoms C4 and C5 of the sphingoid moiety [1,2,3]
We report on the chemical synthesis of a dihydroceramide derivative that prevents the introduction of the double bond into sphingolipids
This structural element is introduced during the last step of ceramide biosynthesis by the enzyme dihydroceramide desaturase (DES1; Scheme 1), a protein bound to the membrane of the Endoplasmic Reticulum [4,5,6,7], encoded by the DEGS1 gene, and myristoylated at its N-terminus [8]
Summary
Most mammalian sphingolipids contain an (E)-configured double bond between the carbon atoms C4 and C5 of the sphingoid moiety [1,2,3]. This structural element is introduced during the last step of ceramide biosynthesis by the enzyme dihydroceramide desaturase (DES1; Scheme 1), a protein bound to the membrane of the Endoplasmic Reticulum [4,5,6,7], encoded by the DEGS1 (degenerative spermatocyte homolog 1) gene, and myristoylated at its N-terminus [8]. Dihydroceramide levels increase in response to resveratrol treatment [19]
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