The first and rate-limiting step in de novo SPH synthesis begins with the condensation of serine and palmitoyl-CoA by SPT to produce 3-ketosphingosine, which is rapidly converted to sphinganine. Sphinganine is then further metabolized by distinct ceramide synthases to dihydroceramides, which can then generate ceramides via dihydroceramide desaturases (DES1). Dihydroceramides can get phosphorylated to sphinganine-1-phosphate or get transported out of the ER to form complex sphingomyelins or glycosphingolipids. To maintain physiologic concentrations of SPHs in the ER, the lysosome can salvage and recycle complex SPHs (sphingomyelins, glycosphingolipids) from plasma membranes. As a consequence of increased ORMDL3 expression, de novo synthesis of SPHs is reduced. Reductions in whole-blood SPH levels have been associated with several features of childhood asthma including increased ASM contractility, airway remodeling, and airway hyperreactivity. GSL, glycosphingolipids; SM, sphingomyelins.