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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Blood Rev. 2022 Apr 9;55:100950. doi: 10.1016/j.blre.2022.100950

Figure 1. Transit map of sphingolipid metabolism.

Figure 1.

Ceramides reside at the canonical center of the sphingolipid metabolism transit map and serve as the central hub for the other sphingolipids. De novo synthesis begins with the condensation of serine and palmitoyl-CoA by the serine palmitoyltransferase (SPT) complex and further processing by 3-ketodihydrosphingosine reductase (KDSR), dihydroceramide synthases (CERS1–6), and dihydroceramide desaturases (DEGS1–2) to generate ceramide (D train). Other methods of generating ceramides include sphingomyelin hydrolysis (S train) by sphingomyelin phosphodiesterases (SMPD1–4) or CERS activity as part of the exit/salvage pathway (E train). Conversely, there are multiple routes to decrease cellular ceramide content. The addition of a phosphocholine head group by the sphingomyelin synthase enzymes (SGMS1–2) generates sphingomyelin (S train). Ceramidases (ASAH1–2 and ACER1–3) hydrolyze ceramide into sphingosine and free fatty acids, and sphingosine kinases (SPHK1–2) phosphorylate sphingosine into sphingosine-1-phosphate (E train). S1P breakdown by sphingosine-1-phosphate lyase (SGPL1) generates phosphoethanolamine and hexadecenal. Ceramide kinase (CERK) phosphorylates ceramide to generate ceramide-1-phosphate (P train). The synthesis of complex glycosphingolipids begins with the action of galactosylceramide synthase (UGT8) to generate galactosylceramides (G train north) or glucosylceramide synthase (UGCG) to generate glucosylceramides (G train south).