SPTLC (serine palmitoyltransferase) enzyme complexes associated with the endoplasmic reticulum membrane catalyze the reaction of palmitoyl-CoA and serine to form 3-ketosphinganine. SPTLC2 and SPTLC3 polypeptides exhibit enzyme activity when either is complexed with SPTLC1. SPTLC1 and 2 are abundant and widely expressed in human tissues, while SPTLC3 is expressed only in a smaller group of tissues and at variable levels. Results of studies in which siRNA was used to reduce levels of the three endogenous mRNAs differentially suggest that SPTLC2 and 3 both encode active serine palmitoyltransferases (Hornemann et al. 2006). Neither human nor mouse SPTLC1 has detectable enzyme activity, but the protein has an essential function, as mutations that disrupt it are associated with hereditary neuropathy (Dawkins et al. 2001). Studies of mouse and hamster proteins support the hypothesis that heterodimerization with SPTLC1 stabilizes SPTLC2 (or 3) and mediates its localization to the endoplasmic reticulum membrane (Hanada et al. 2000; Weiss and Stoffel 1997). Yeast SPTLC has a third small subunit (Tsc3) associated that is required for maximal SPT activity (Gable et al. 2000). Analyses of complexes from cultured human cells and placenta suggested that the SPTLC heterodimers might associate into larger complexes (Hanada et al. 2000; Weiss and Stoffel 1997; Hornemann et al. 2006, 2007). Two novel small subunits (SPTSSA and SPTSSB) were identified, both of which enhance SPTLC activity >10-fold when bound to either of the SPTLC heterodimers (Han et al. 2009). Orosomucoid (ORM) proteins, first identified in yeast, associate with and negatively regulate SPTLC activity (Breslow et al. 2010, Han et al. 2010). The 3 human ORM proteins similarly bind and negatively regulate SPTLC activity (Breslow et al. 2010).