Sphingomyelinase Mechanism

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

Fig. 5.2 General-base catalytic mechanism for bacterial sphingomyelinase. Redrawn from Ref. [73].

Martin, S. F., Sawai, H., Villalba, J. M., and Hannun, Y. A. Redox regulation of neutral sphingomyelinase-1 activity in HEK293 cells through a GSH-dependent mechanism. Arch Biochem Biophys 459 (2007) 295-300. 

Dumitru, C.A., and Gulbins, E., TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene, 25 (2006) 5612-5625. 

Oxysterols have diverse roles in cholesterol efflux, a critical topic in foam cell biology. On the one hand, cells incubated with 7-ketocholesterol and 25-hydroxycholesterol have decreased cholesterol efflux. Possible mechanisms include inhibition of membrane desorption of cholesterol or phospholipids or, as mentioned above, inhibition of lysosomal sphingomyelinase leading to lysosomal sequestration of cholesterol (M. Aviram, 1995). On the other hand, the conversion of cholesterol by macrophage sterol 27-hydroxylase to 27-hydroxycholesterol and 3[l-hydroxy-5-cholestenoic acid, which are efficiently effluxed from cells, has been proposed to promote sterol efflux from foam cells (1. Bjorkhem,... 

Tabas, I., Li, Y., Brocia, R.W., Xu, S.W., Swenson, T.L., Williams, K.J. 1993. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein (a) retention and macrophage foam cell formation. J Biol. Chem. 268 20419-20432. 

Perivascular and intra-arterial administration of neutral sphingomyelinase or exogenous short-chain ceramide resulted in a potent concentration-dependent constriction of cortical venules, followed by increased venular waU permeability, post-capillary venule rupture and micro-hemorrhaging (Altura et al, 2002). Treatment with antioxidants, calcium channel blockers and inhibitors of nuclear factor-KB activation could attenuate the effects of neutral sphingomyelinase and ceramide. These results suggest that ceramide can play a role in vasoconstriction and may be involved in the mechanisms resulting in brain injury and stroke. 

Altura, BM, Gebrewold, A, Zheng, T and Altura, BT (2002) Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothehal interactions in cerebral venules in the intact rat brain Insight into mechanisms and possible relation to brain injury and stroke. Brain Res Bull, 58, 271-278. 

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