Ingrid 't Hart

11 Introduc�on 1 Figure 4. Biosynthesis of globo-series GSLs by mammalian glycosyltransferases. 1.1.2 Ganglio-series GSLs The ganglio-series GSL synthe�c pathway starts with the addi�on of an α2,3-linked sialic acid to Lac-Cer by ST3Gal5 to form GM3-Cer (Fig. 5). 24 The synthesis of ganglio-series SGLs commences with the 3-O-sulfa�on of Lac-Cer, providing SM3-Cer. SM3-Cer can be used for further enzyma�c modifica�ons in a similar manner as for GM3-Cer. 8 A high variety of ganglio-series GSL subclasses can be synthesized star�ng from Lac-Cer or GM3-Cer: the 0-, a-, b- and c- series. 10 Here, we will focus on a subset of gangliosides derived from the a- and b-series. In the a-series GM3-Cer can be extended with an β1,4- acetyl galactosamine by B4GalNT1 to form GM2-Cer. 25 The β1,3-galactosyltransferase B3GalT4 extends GM2-Cer to form GM1(a)-Cer. 26 GM1(a)-Cer can be further decorated with sialic acids by the sialyltransferases ST3Gal2 or ST3Gal3 to form GD1a-Cer. 27 GD1a- Cer can be further sialylated by the α2,8-sialyltransferase ST8Sia5 to form GT1a-Cer or by the α2,6-sialyltransferase ST6GalNAc5 (ST6GalNT5) to form GT1aα-Cer. 28 The b-series start with the addi�on of an α2,8-linked sialic acid by ST8Sia1 to GM3-Cer to form GD3- Cer. 29 GD3-Cer can then be extended by the same enzymes as for the a-series to form GD2-Cer, GD1b-Cer, GT1b-Cer, GQ1b-Cer and GQ1bα-Cer. 10 Figure 5. The full biosynthesis of the a-series ganglio-series GSLs and the ini�al step for the b-series GSLs. GD3 can be extended by the glycosyltransferases described for a-series. Cer β1,3 α1,4 β1,4 β1,3 MSGb5 α2,3 Cer β1,3 α1,4 β1,4 β1,3 DSGb5 α2,3 α2,6 A4GalT Cer β1,3 α1,4 β1,4 β1,3 Globo-H α1,2 Cer β1,3 α1,4 β1,4 β1,3 Gb5 Lac Cer β1,4 Gb3 Cer α1,4 β1,4 B3GalNT1 B3GalT5 Cer β1,3 α1,4 β1,4 Gb4 Fut1/Fut2 ST3Gal2 ST6GalNAc6 α2,8 α2,3 β1,4 GT1aα β1,4 β1,3 α2,3 Cer ST3Gal5 ST8Sia5 α2,3 β1,4 GM1a β1,4 β1,3 Cer α2,3 β1,4 GM2 β1,4 Cer β1,4 Lac Cer α2,3 β1,4 GM3 Cer B4GalNT1 α2,3 β1,4 GD3 Cer α2,8 B3GalT4 ST8Sia1 ST3Gal2/3 α2,3 β1,4 GD1a β1,4 β1,3 α2,3 Cer