In general, SLSs are Golgi-resident transmembrane proteins, presumed to have 6 transmembrane domains with the active site facing the Golgi lumen (Holthuis et al. 2006; Sutterwala et al. 2008). Those orthologues identified in kinetoplastids demonstrated two conserved regions (CGDX3SGHT & HYTXDVX3YX6FX2YH) with respect to the animal SM synthases (Huitema et al. 2004; Denny et al. 2006). These regions contain the so-called the catalytic triad (two Histidines and one Aspartate residues) that mediates a nucleophilic attack on lipid phosphate ester during the transferase/hydrolase activity (Mina et al. 2010). Apicomplexan orthologues form a separate evolutionary clade, yet retain the catalytic triad (Denny et al. 2006; Pratt et al. 2013), as does the fungal orthologue AUR1p (Heidler & Radding, 2000). Further evidence for the essentiality of these residues was provided when mutation of the active histidine of the triad was shown to deactivate fungal IPC synthase and mammalian SM synthase-related activity (Levine et al. 2000; Vacaru et al. 2009). Furthermore, recently it has been shown that substrate selectivity, and so the diversity of SLS activity, may depend on key residues close to the transferase active residues or on a luminal loop of the protein (Sevova et al. 2010; Kol et al. 2017).