Brodesser Susanne, Kolter Thomas
CECAD Cologne Platform Lipidomics, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstraße 19-21, 50935 Cologne, Germany.
J Lipids. 2011;2011:724015. doi: 10.1155/2011/724015. Epub 2010 Dec 5.
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.
大多数哺乳动物鞘脂含有一个4,5-(E)-双键。我们报道了一种二氢神经酰胺衍生物的化学合成，该衍生物可阻止双键引入鞘脂中。通过用亚甲基正式取代鞘氨醇骨架5位和6位的氢原子，对母体结构进行最小程度的改变，从而得到一种培养细胞中二氢神经酰胺去饱和酶的抑制剂。在存在10 - 50 μM化合物(1)的情况下，生物合成形成的二氢神经酰胺以及令人惊讶的植物神经酰胺的水平会升高，同时神经酰胺水平降低。细胞通过提高鞘氨醇形成所需酶的mRNA水平来应对不饱和鞘脂的缺乏。与此同时，对增殖和分化标志物的分析表明，鞘脂双键是维持细胞分化状态所必需的。
