Exploring the therapeutic landscape of sphingomyelinases

Sphingosine, ceramide, sphingosine-1-phosphate, and other related sphingolipids have emerged as important bioactive molecules involved in a variety of key cellular processes such as cell growth, differentiation, apoptosis, exosome release, and inter- and intracellular cell communication, making the pathways of sphingolipid metabolism a key domain in maintaining cell homeostasis (Hannun and Obeid, Trends Biochem Sci 20:73–77, 1995; Hannun and Obeid, Nat Rev Mol Cell Biol 9:139–150, 2008; Kosaka et al., J Biol Chem 288:10849–10859, 2013). Various studies have determined that these pathways play a central role in regulating intracellular production of ceramide and the other bioactive sphingolipids and hence are an important component of signaling in various diseases such as cancer, diabetes, and neurodegenerative and cardiovascular diseases (Chaube et al., Biochim Biophys Acta 1821:313–323, 2012; Clarke et al., Adv Enzyme Regul 51:51–58, 2011b; Horres and Hannun, Neurochem Res 37:1137–1149, 2012). In this chapter, we discuss one of the major enzyme classes in producing ceramide, sphingomyelinases (SMases), from a biochemical and structural perspective with an emphasis on their applicability as therapeutic targets.