Ingrid 't Hart

8 Chapter 1 1 1.1 Glycosphingolipids: gangliosides and sulfoglycolipids Glycosphingolipids (GSLs) are glycans conjugated to a lipid (ceramide), which is covalently linked to the reducing end of the carbohydrate. The first discovered GSL was galactosylceramide (Gal-Cer) in 1884 from brain �ssue and its structure proved so difficult to determine that it was named a�er the equally enigma�c Egyp�an Sphinx. Currently, hundreds of different oligosaccharide moie�es have been discovered among GSLs and various ceramide subtypes increase the diversity of GSLs. The most common sphingoid base of ceramide in mammals is D- erythro -sphingosine (d18:1) (sphingosine). The fa�y acid of the ceramide can vary in chain length, contain an α-hydroxyl group or can be (poly)unsaturated. 1,2,3,4 Furthermore, GSLs can be divided in neutral and nega�vely charged subclasses. The nega�vely charged subclass covers GSLs with one or more sialic acids (gangliosides) and sulfated glycolipids (sulfoglycolipids or sulfa�des; SGLs). Notably, sialyla�on or sulfa�on o�en occurs at the same posi�on of a glycolipid, as is the case for ganglioside GM1a and sulfoglycolipid SM1a (Fig. 1). Figure 1. Ganglioside GM1a (le�) and sulfoglycolipid SM1a (right). Ceramide (middle) mainly contains (D- erythro -)sphingosine (d18:1) in mammals (black). The carbon chain length of the fa�y acid (grey) of the ceramide can vary in length (R = 13 to >29), can be unsaturated or bear an α-hydroxyl group. Glycosphingolipids contain a polar par (the sugar) and an apolar part (the lipid) and are mostly found in the cell membrane with the glycan part facing the extracellular environment (Fig. 2). 1,2,3,5 GSLs form clusters in the membrane, called lipid ra�s, together with other lipids such as cholesterol and sphingomyelin and proteins such as GPI- anchored proteins and receptor tyrosine kinases. 3,5,6 Interac�ons of GSLs can take place with structures residing in the same membrane ( cis interac�ons) or with extracellular components ( trans interac�ons). 3,4 All cells in our body synthesize GSLs to a different extent. 3 S�ll, GSLs are mainly found in nervous �ssues where they are important for the integrity and regenera�on of nerves. 5 Besides nervous �ssue, GSLs are also found on different types of innate and adap�ve immune cells such as lactosylceramide (Lac-Cer) on neutrophils and a-series and 0-series gangliosides on CD4+ and CD8+ T cells. 1,6 Different studies have shown that GSLs are important for proper development in mul�cellular organisms, where deficiencies or altera�ons can cause severe neurological, immunological and epithelial malfunc�ons. 3,7 O OH O - O 3 SO OH O HO OH O AcHN O HO OH HO HO O OCer O OH HO HO O OH O O OH O HO OH O AcHN O HO OH HO HO O OCer O OH HO HO O HO HO HO NHAc HOOC Ceramide HN OH C 13 H 27 R O SM1a GM1a OH