Sphingomyelinase Kinase Inhibitors

Ceramide, a sphingosine-based lipid-signaling molecule, has gained serious attention as an important signaling molecule in cell cycle, cell differentiation, apoptosis, and immune response. Ceramide is generated either through de novo synthesis mediated by ceramide synthase or through hydrolysis of membrane sphingomyelin by an acid or neutral sphingomyelinase. Acid and neutral sphingomelinases differ in their ion dependence, pH optima, and cellular localization. Recent evidence suggests that the activation of a non-specific lipid scramblase during apoptosis induces the flipping of sphingomyelin from the cell surface to the cytoplasm side of the plasma membrane where it is cleaved by neutral sphingomyelinase to generate ceramide. The production of ceramide induces blebbing of the plasma membrane and aids in rapid engulfment by phagocytes. Neutral sphingomyelinase-released ceramide has also been shown to be essential for capping of L-selectin in lymphocytes.

Some evidence exists indicating that acid sphingomyelinase deficient cells have defects in apoptotic signaling pathways. Sphingomyelin is usually rapidly broken down in the late endosomes and lysosomes. Hence, in acid sphingomyelinase deficiency, sphingomyelin may be kinetically trapped in lysosomes and disrupt endocytic trafficking of raftassociated cell surface signaling molecules. Defects in acid sphingomyelinase have also been linked to lysosomal storage disease known as Niemann-Pick disease, which results in progressive enlargement of liver and spleen.

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Tomiuk, S., et al. 1998. Proc. Natl. Acad. Sci. USA 95, 3638.