Neutral sphingomyelinases

This small and barely known group of sphingomyelinases includes an enzyme found in fhe cytosol of HL-60 cells by Okazaki et al. [81], and fhe 53 kDa isoform of nSMase found by Ghosh et al. [48] in rabbit skeletal muscle. 

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Figure 1. Ceramide mediated apoptosis signaling, Recent investigations hypothesize that, at least for drug induced apoptosis, the src kinase Lyn is activated and recruited to plasma membrane rafts. There it binds to and activates a neutral sphingomyelinase (SMase) within minutes. This initial rise in ceramide levels initiates an apoptotic cascade. Howevo- several cellular events can inhibit ceramide production (by blocking sphingomyelinase activation or clearing out ceramide accumulation through increased metabolisation) and therefore contribute to cellular resistance/survival.

Chmura, S. J., Nodzenski, E., Weichselbaum, R. R., and Quintans, J., 1996, Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase. Cancer Res. 56 2711-2714. 

Mansat, V., Laurent, G. Levade, T., Bettaieb, A., and Jaffrezou, J.P., 1997a, The protein kinase C inhibitors phorbol ester and phosphatidylserine block neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. Cancer Res. 57 5300-5304. 

Tamiya-Koizumi, K., Umekawa, H., Yoshida, S., and Kojima, K., 1989, Existence of Mg " "-dependent, neutral sphingomyelinase in nuclei of rat ascites hepatoma cells. J. Biochem. 106 593-598,... 

Veldman, R. J., Maestre, N., Aduib, O. M., Medin, J. A., Salvayre, R., and Levade, T., 2001, A neutral sphingomyelinase resides in sphingolipid-enriched microdomains and is inhibited by the caveolin-scaffolding domain potential implications in tumor necrosis factor signaling. Biochem. J. 355 859-868. 

Jaffrezou, J. P., Maestre, N., de Mas-Mansat, V., Bezomhes, C., Levade, T., and Laurent, G., 1998, Positive feedback control of neutral sphingomyelinase activity by cerattride. Faseb J 12 999-1006. 

Samet, D., and Barenholz, Y., 1999, Characterization of acidic and neutral sphingomyelinase activities in crude extracts of HL-60 cells. Chem Phys Lipids 102 65-77. 

Wu, M., Harvey, K., Ruzmeto, N., Welch, Z., Sech, L., Jackson, K., Stillwell, W., Zaloga, G., and Siddiqui, R. (2005). Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway. Int.. Cancer 117, 340-348. 

Uchida R, Tomoda H, Arai M, Omura S (2001) Chlorogentisylquinone, a New Neutral Sphingomyelinase Inhibitor, Produced by a Marine Fungus. J Antibiot 54 882... 

Marchesini N. and Hannun Y. A. (2004). Acid and neutral sphingomyelinases roles and mechanisms of regulation. Biochem. Cell Biol. 82 27 14. 

Chatterjee, S., 1994, Neutral sphingomyelinase action stimulates signal transduction of tumor necrosis factor-alpha in the synthesis of cholesteryl esters in human fibroblasts. J. Biol. Chem. 269 879-882... 

The fungal metabolite scyphostatin (Fig. 7) is a potent, reversible inhibitor of membrane-bound Mg +-dependent neutral sphingomyelinase (nSMase), thereby interfering with the generation of ceramide (102, 103). The activity of nSMases is sensitive to the cellular redox state, for example, the ratio of glutathione in the reduced versus the oxidized form (104, 105). The famesyltransferase inhibitor manumycin A, a polyenamide produced by the Streptomyces species, also inhibits nSMase irreversibly (106). 

Nara F, Tanaka M, Masuda-Inoue S, Yamasato Y, Doi-Yoshioka 119. H, Suzuki-Konagai K, Kumakura S, Ogita T. Biological activities of scyphostatin, a neutral sphingomyelinase inhibitor from... 

Hannun YA. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-a-induced cell death J. Biol. Chem. 1998 273 11313-11320. 121. 

HJ, Giannis, A. Manumycin A and its analogues are irreversible inhibitors of neutral sphingomyelinase. ChemBioChem. 2001 2 141-143. 123. 

Wascholowski V, Giannis A. Sphingolactones selective and irreversible inhibitors of neutral sphingomyelinase. Angew. Chem. Int. Ed. 2006 45 827-830. 

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