Ingrid 't Hart

10 Chapter 1 1 Figure 3. GSL subclasses, based on their glycan composi�on, adapted from: Schnaar et al., 2017. 3 Highlighted are globo- and ganglio-series GSLs. 1.1.1 Globo-series GSLs The first extension towards globo-series glycosphingolipids is performed by the α-1,4 galactosyltransferase A4GalT to form Gb3-Cer (also known as ceramide trihexoside, CD77 or P K an�gen) from Lac-Cer (Fig. 4). 12 Gb3-Cer can be further extended by β1,3- acetylgalactosaminyltransferase B3GalNT1 to form Gb4-Cer (P an�gen). Gb4-Cer forms the acceptor substrate for β1,3-galactosyltransferase B3GalT5, providing Gb5-Cer (SSEA-3). 13,14 Gb5 can be decorated with fucose by the enzymes FUT1 or FUT2 to form α1,2-fucosylated Globo-H. 15 Apart from that, Gb5-Cer can be extended by one or more sialic acids. Addi�on of α2,3-Neu5Ac to the reducing galactose residue of Gb5-Cer by ST3GAL2 leads to the forma�on of MSGb5 (SSEA-4). 16 An addi�onal 2,6-Neu5Ac can be transferred onto the internal GalNAc of MSGb5-Cer by ST6GalNAc6 to form DSGb5-Cer. 17 Although li�le is known of globo-series SGLs, gal-3- O -sulfotransferases were studied for their ability to install 3- O -sulfates on globo-series oligosaccharides. From these studies it was found that both Gal3ST2 and Gal3ST4 are able to install a sulfate on the non- reducing trisaccharide of Gb5 (Galβ1,3GalNAcβ1,3GalαOMe). 18,19 The smallest glycolipid of the globo-series GSLs, Gb3-Cer, is known to be involved in a variety of diseases. Gb3-Cer, and to a lesser extend Gb4-Cer, are known to be a receptor for Shiga toxins (also called verotoxin). 20 Furthermore, accumula�on of Gb3 is a biomarker for Fabry Disease: a lyosomal storage disorder, caused by a deficiency in α-galactosidase. 21 Next to that, Gb3-Cer on monocytes (mainly CD4 + T-cells) is proposed to bind gp120 on HIV, however whether this interac�on induces or inhibits HIV is not fully known. 22 Gb4-Cer is a major glycolipid component of erythrocytes and has been reported to bind epidermal growth factor receptor (EGFR), also for this GSL li�le is known about the exact func�on. 5,23 GSLs of the globo-series are known to be the first to appear during embryogenesis; in par�cular Gb5-Cer (SSEA-3) and MSGb5-Cer (SSEA-4) have been iden�fied as embryonic stem cell markers. 24 Ceramide β1,3 β1,4 β1,4 ganglio lacto neolacto globo isoglobo mollu arthro Series sugars and linkages Ceramide β1,3 β1,3 β1,4 Ceramide β1,4 β1,3 β1,4 Ceramide β1,3 α1,4 β1,4 Ceramide β1,3 α1,3 β1,4 Ceramide β1,2 α1,3 β1,4 Ceramide β1,4 β1,3 β1,4 GalNAc Gal Glc GlcNAc Man