Handbook of Glycosyltransferases and Related Genes pp 1673-1679 | Cite as
Map 3: Biosynthetic Pathways of Glycosphingolipids
Glycosphingolipids (GSLs) are a large and heterogeneous family of sphingolipids that form complex patterns on eukaryotic cell surfaces. The diverse structures of GSLs are depending on their structural combinations in long-chain (sphingoid) bases, amide-linked fatty acids, and hundreds of headgroup variants. The subcellular biosynthetic machinery of GSLs is summarized in Fig. 149.1. Sphingolipids are generated by attachment of different polar headgroups at the primary alcohol group (C1–OH) of a ceramide molecule at the endoplasmic reticulum (ER). Modification of a ceramide by addition of one or more sugars yields complex GSLs. Glyco-chains of GSLs are mainly synthesized in the lumen of Golgi apparatus. The exception is glucosylceramide (GlcCer) and galactosylceramide (GalCer), which are biosynthesized on the cytoplasmic leaflet of Golgi membrane and on the inner leaflet of ER, respectively. Most of GSLs are biosynthesized from GlcCer with only limited members from GalCer. To execute the further elongation, GlcCer has to be translocated from the cytosolic leaflet to the inner leaflet of Golgi membrane by a specific translocase, which has not been identified. GalCer also has to be traveled from the inner leaflet of ER to the lumen of Golgi to synthesize NeuAc-GalCer (GM4) and sulfated GalCer (SM4). This topological orientation of the catalytic sites of glycosyltransferases is supported by the structures of glycosyltransferases. GlcCer synthase is type III membrane protein with an N-terminal signal-anchor sequence, and other glycosyltransferases are type II membrane proteins with an N-terminal membrane-spanning domain and catalytic domains at the C-terminal region. Lactosylceramide (LacCer) plays a pivotal role as a precursor for the synthesis of complex GSLs. The common LacCer structure is then elongated by different glycosyltransferases, thereby defining the six classes of GSLs as Gala, Globo (Gb), Isoglobo (iGb), Ganglio (Gg), Lacto (Lc), and Neolacto (nLc) subtypes according to their specific saccharide core structures. The detailed maps for biosynthetic pathways of each class of GSLs in mammals are summarized as symbolized structures (Figs. 149.2–149.8). Recently, it has been demonstrated that the sialylation of GalCer to form GM4 is catalyzed by GM3 synthase (ST3Gal5).