Considering the central position of CER, the druggability of SL metabolism revolves around dysregulation of ‘Ceramide Homeostasis’ (Young et al. 2012) which in turn leads to ripple effects perturbing the balance between the pro-apoptotic CER and the mitogenic diacylglycerol (DAG), consequently determining cell fate (Fig. 2) – a mechanism that has been associated with resistance to anti-cancer treatments (Ségui et al. 2006) and has been reported in protozoan parasites, e.g. Plasmodium (Pankova-Kholmyansky et al. 2003; Labaied et al. 2004). The characterisation of several key enzymes involved in SL de novo biosynthesis has revealed divergence between mammalian and protozoan species. Thus, attention has been given to the exploitation of the SL biosynthetic pathway (parasite and/or host) for new drug targets or regimens (Sugimoto et al. 2004; Zhang et al. 2005; Denny et al. 2006; Tanaka et al. 2007; Pruett et al. 2008; Mina et al. 2009; Tatematsu et al. 2011; Young et al. 2012). Fig. 2.Schematic representation of de novo sphingolipid metabolism. Three key steps are highlighted: (1) SPT, evolutionary divergent in T. gondii; (2) CerS, fewer isoforms in protozoan parasite (c.f. 6 isoforms in mammals); SLS, while predominantly synthesising SM in mammals and to a lesser extent EPC, orthologues in protozoan parasites (Leishmania spp., T. brucei, T. cruzi and T. gondii) can synthesise IPC, an activity that is absent from mammalian cells and the target of the highly specific fungal inhibitors shown. The scheme also illustrates the differential cellular effects of ceramide vs DAG (diacylglycerol). Accumulation of ceramide elicits an apoptotic response while increasing concentrations of DAG promotes cell growth. CerS, ceramide synthase; GluCerS, glucosylceramide synthase; SLS, sphingolipid synthase; SPT, serine palmitoyltransferase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; SM, sphingomyelin; EPC, ethanolamine phosphorylceramide and IPC, inositol phosphorylceramide.