Glycosphingolipid biosynthesis (ceramide -> GlcCer/GalCer -> LacCer -> ganglio/globo/lacto series)

Glycosphingolipids are ceramide-anchored glycans that cover the outer leaflet of the plasma membrane, clustering in lipid rafts and serving as blood-group antigens, cell-adhesion and signalling receptors, and receptors hijacked by toxins and pathogens. Their synthesis is a Golgi-based branching tree built on ceramide. Two committed glycosylations start the two major limbs: glucosylceramide synthase UGCG adds glucose to ceramide (glucosylceramide, GlcCer, the trunk of the ganglio/globo/lacto glycosphingolipids), while UGT8 in the ER adds galactose to make galactosylceramide (GalCer, precursor of the myelin galactolipids and sulfatide). GlcCer is galactosylated by the beta-1,4-galactosyltransferases B4GALT5 (major) and B4GALT6 to lactosylceramide (LacCer), the central branch point. From LacCer three series diverge: the GANGLIO series begins when the sialyltransferase ST3GAL5 (GM3 synthase) adds sialic acid to make GM3, which ST8SIA1 (GD3 synthase) can further sialylate to GD3, and which B4GALNT1 (GM2/GD2 synthase) elongates with GalNAc toward the complex a-/b-series gangliosides; the GLOBO series begins when A4GALT (Gb3/CD77 synthase) adds an alpha-galactose to make globotriaosylceramide (Gb3, the Shiga-toxin receptor and Pk antigen), which B3GALNT1 (globoside synthase) extends to globoside (Gb4, the P antigen); and the (neo)LACTO series begins when B3GNT5 adds GlcNAc to make lactotriaosylceramide (Lc3), the scaffold for Lewis/blood-group glycans. Inherited defects at almost every node cause disease: UGCG is the drug target for glycosphingolipidoses, ST3GAL5 deficiency causes GM3-synthase-deficiency epileptic encephalopathy, B4GALNT1 deficiency causes hereditary spastic paraplegia (SPG26), and A4GALT/B3GALNT1 variants define the P blood-group system.