Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide.
Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide.
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DOI：
10.1016/s0021-9258(19)74304-x
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发表时间：
1993-12
期刊：
影响因子：
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通讯作者：
A. Bielawska;H. M. Crane;Dennis C. Liotta;L. Obeid;Yusuf A. Hannun
中科院分区：
文献类型：
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作者：
A. Bielawska;H. M. Crane;Dennis C. Liotta;L. Obeid;Yusuf A. Hannun
神经酰胺作为推定的第二信使出现，介导细胞外试剂对细胞生长和分化的作用（Okazaki，T.，Bielawska，A.，贝尔河，巴西-地M.，和Hannun，Y.（1990）J.Biol.Chem.265，15822-15831）和程序性细胞死亡（Obeid，L. M.，利纳迪克角M.，卡罗拉克湖一、和Hannun，Y. A.（1993）Science 259，1769-1771）。本研究合成了C2-神经酰胺和二氢神经酰胺的八个立体异构体，并对其细胞活性进行了研究。C2-神经酰胺的四种立体异构体在抑制细胞生长和诱导细胞凋亡方面具有活性，效力略有差异。另一方面，对于C2-二氢神经酰胺，只有苏型化合物在这些测定中有活性，而苏型化合物完全无活性。因此，在两种天然存在的分子中，D-邻位-神经酰胺的类似物（具有4-5个反式双键）是活性的，而D-邻位-二氢神经酰胺的类似物是无活性的。这些结果证明了神经酰胺作用的特异性，并表明双键的引入对于赋予神经酰胺的生化和生物活性是至关重要的。
Ceramide is emerging as a putative second messenger mediating effects of extracellular agents on cell growth and differentiation (Okazaki, T., Bielawska, A., Bell, R. M., and Hannun, Y. (1990) J. Biol. Chem. 265, 15822-15831) and programed cell death (Obeid, L. M., Linardic, C. M., Karolak, L. A., and Hannun, Y. A. (1993) Science 259, 1769-1771). In this study, the eight stereoisomers of C2-ceramide and dihydroceramide were synthesized, and their cellular activity was investigated. The four stereoisomers of C2-ceramide were active in inhibition of cell growth and induction of apoptosis with modest differences in potency. On the other hand, with C2-dihydroceramide only the threo compounds were active in these assays whereas the erythro compounds were totally inactive. Thus, of the two naturally occurring molecules, the analog of D-erythro-ceramide (with the 4-5 trans double bond) was active, whereas the analog of D-erythro-dihydroceramide was inactive. These results demonstrate the specificity of ceramide action and suggest that the introduction of the double bond is critical for imparting the biochemical and biological activity of ceramide.