Sphingoid-backbone lipids — sphingomyelin (membrane), ceramide (signaling + apoptosis induction), glucosylceramide (precursor for complex glycosphingolipids + gangliosides). De novo synthesis: serine + palmitoyl-CoA → 3-ketosphinganine (SPT) → sphinganine → ceramide (CerS). Sphingomyelin synthase + glucosylceramide synthase build the complex lipids. Lysosomal storage diseases of sphingolipid degradation: Gaucher (glucocerebrosidase), Niemann-Pick A/B (acid sphingomyelinase), Fabry (α-galactosidase A), Krabbe (galactocerebrosidase), Tay-Sachs (β-hexosaminidase A). Eliglustat / miglustat are oral glucosylceramide synthase inhibitors for Gaucher (substrate reduction therapy, vs ERT alternatives).
Organ Systems
nervous
immune-hematologic
Pathway Steps
palmitoyl-coa → 3-ketosphinganine — via serine palmitoyltransferase (SPT) — condenses serine + palmitoyl-CoA. Serine palmitoyltransferase condenses serine with palmitoyl-CoA — the committed, rate-limiting entry to sphingolipid synthesis. SPT mutations cause hereditary sensory neuropathy (HSAN1) via toxic deoxy-sphingolipids.
3-ketosphinganine → ceramide — via multi-step (3-KSR + ceramide synthase + desaturase). Ceramide is the central hub of sphingolipid metabolism — both a building block and a pro-apoptotic, stress/senescence second messenger. Ceramide synthases (CerS1–6) differ by acyl-chain length, giving tissue-specific ceramide species.
ceramide → sphingomyelin — via sphingomyelin synthase (phosphocholine from PC). Sphingomyelin synthase transfers phosphocholine from PC onto ceramide, making the major membrane sphingolipid (abundant in myelin and lipid rafts) and generating DAG — coupling sphingolipid and glycerolipid signaling.
ceramide → glucosylceramide — via glucosylceramide synthase (UGCG) — ELIGLUSTAT TARGET. Glucosylceramide synthase begins glycosphingolipid/ganglioside synthesis and is the eliglustat target. Defects in the reverse lysosomal catabolism cause sphingolipidoses — Gaucher (glucocerebrosidase) and Tay-Sachs (hexosaminidase A).