Glycosphingolipids

The subclasses of glycosphingolipids, also called series, are defined by respective di- or trisaccharide cores. The mains series of vertebrates are the globosides, lactosides and gangliosides. The glycan structures found on glycosphingolipids are often similar to those found on O-GalNAc glycoproteins since several Golgi glycosyltransferases can elongate both types of glycoconjugates.

FIG: GSL CORE STRUCTURES

The three main series are further divided into sub-groups based on the fourth sugar transferred, thus distinguishing isoglobosides from globosides and lactoneosides from lactosides. To make things even more complicated, additional subclasses of glycosphingolipids like the arthro- and the mollu-series occur only in invertebrates. These two series include b4-linked Man as second sugar, which is transferred by the b1-4 Man-transferase enzyme called egghead in Drosophila. Interestingly, the natural insecticide BT toxin uses arthro-series glycosphingolipids as receptors, thus explaining the resistance of vertebrates to this class of toxins. Glycosphingolipids of the gala- and muco-series are also found in vertebrates, although in small amounts and little is known about the functional relevance of these series. Sulfated glycosphingolipids are classified as sulfatides, of which the major form in mammals is 3-O sulfogalactoceramide, also called cerebroside 3-sulfate. This compound is a major constituent of myelin lipids and is also found in the retina and in smaller amounts in kidney tissue. Sulfatides also include longer chains of up to four sugars.

FIG: EXTENDED GSL CLASSES 

The first step in the biosynthesis of glycosphingolipids takes place at the cytosolic side of the cis-Golgi membrane, where the enzyme UDP-Glc ceramide glucosyltransferase (UGCG) transfers Glc to ceramide. Since the product glucosylceramide has to flip to the luminal side of the Golgi membrane to be further elongated, it has been postulated that UGCG may act as flippase as well. However, neither the flipping activity of UGCG, nor the identity of a dedicated flippase protein could be confirmed to date. UGCG is also unique among Golgi glycosyltransferases in regard to its type-III transmembrane topology (N-terminal anchor sequence and cytosolic C-terminal catalytic domain). The essential role of glycosphingolipids in mammalian development was confirmed by the disruption of the Ugcg gene in mice, which resulted in lethality by embryonic day 7.5.

FIG: UGCG FLIPPING

Glucosylceramide is further elongated in the Golgi apparatus through the coordinated action of multiple glycosyltransferases, thereby yielding close to 400 different glycosphingolipid structures. Some of these glycosyltransferases are specific for glycolipids while others act also glycoprotein substrates. When considering the biosynthesis of glycosphingolipids, please remember that galactosylceramide is synthesized in the ER by a dedicated ceramide galactosyl­transferase (CGALT) enzyme. Galactosylceramide is then transported to the plasma membrane by transiting to the Golgi apparatus where it mainly remains non-elongated. Galactosylceramide is mainly produced by oligodendrocytes and Schwann cells and plays an essential role in myelin function and stability. In fact, Cgalt-null mice exhibit altered nerve conduction which progressively leads to tremors and paralysis. The animals die by the end of the myelination period by an age of about one month.

The series of gangliosides shows a complex pattern of sialylation, which challenges the definition of a rationale nomenclature. In spite of relying on a logical system, the current nomenclature of gangliosides certainly does not contribute to the popularity of glycobiology. Ready to dive? Gangliosides are abbreviated by symbols of two letters and one number. The first letter is always G, which stands for gangliosides. The second letter is either A, M, D, T, Q or P, which indicates the number of Sia (A: asialo-, M: monosialo-, D: disialo-, etc). The number N reflects the length of the neutral sugar chain, where N is equal to 5 minus the length of this neutral sugar chain. Now take a deep breath and relax. According to this system, the ganglioside GM3 has one Sia and two neutral sugars, whereas the ganglioside GQ1c has four Sia and four neutral sugars. The suffix “c” is used to denote that the proximal sialylated chain includes three Sia residues. Easy, isn’t it? 

FIG: GANGLIOSIDES

The structural complexity and specificity of some glycosphingolipids for some cell types has made them suitable cell markers. For example, several stage-specific embryonic antigens (SSEA) are glycosphingolipids that are expressed on mouse cells at specific embryonic stages. The Forssman antigen is a glycosphingolipid with a terminal GalNAc(a1-3)GalNAc structure that is normally not found on human cells. However, some studies have claimed that the Forssman antigen could represent a tumor-associated antigen since it was detected on some gastrointestinal tumors in humans. The most famous polymorphic markers in humans, the ABO blood group antigens, are also glycosphingolipids (see below).

FIG: GSL AS CELL MARKERS