Glycosphingolipids

Glycobiology Analysis Manual, 2nd Edition

Structure

Glycosphingolipids (sometimes called glycolipids) have been found in lower and higher eukaryotic sources. They are composed of a glycan structure attached to a lipid tail that contains the sphingolipid ceramide. The basic structure for a glycosphingolipid is a monosaccharide, usually glucose or galactose, attached directly to a ceramide molecule and resulting in, respectively, glucosylceramide (glucocerebroside; GlcCer) or galactosylceramide (galactocerebroside; GalCer). The core glycan structure may be extended by additional monosaccharides. This combination structure results in an amphiphilic molecule with a hydrophilic carbohydrate region and a hydrophobic lipid region. In addition to variations in the structure of the glycan, the ceramide structure may also show variation. The fatty acid attached to the sphingosine may contain carbon chain lengths from C14 to C24 and vary in degree of unsaturation and/or hydroxylation.

Abbreviations for the oligosaccharide chains of glycosphingolipids have been recommended by IUPAC to make the nomenclature less complex.1 The recommended root names are shown in Table 1.

 

Root Name Symbol Root Structure
IV   III   II   I
Ganglio- Gg Galb3GalNAcb4Galb4Glc-
Lacto-
Lc Galb3GlcNAcb3Galb4Glc-
Neolacto (Lactoneo) nLc (Lcn) Galb4GlcNAcb3Galb4Glc-
Globo- Gb GalNAcb3Gala4Galb4Glc-
Isoglobo- iGb GalNAcb3Gala3Galb4Glc-
Mollu- Mu GlcNAcb2Mana3Manb4Glc-
Arthro- At GalNAcb4GlcNAcb3Manb4Glc-

Table 1. Root Names, Symbols, and Root Structures for Glycosphinoglipid Chains.

The outer extensions of glycosphingolipids contain sugars including fucose, glucuronic acid, and sialic acid, and blood group structures that are similar to those of O- and N-glycans. Like O- and N-glycans, modifications such as 9‑O-acetylation, N-deacetylation of sialic acids, or O-sulfation and O-acylation of galactose residues may also be present. Glucosyl ceramide and galactosyl ceramide are neutral, while glycosphingolipids containing sulfate, phosphate, or sialic acid residues are acidic and have a negative net charge. Gangliosides are glycosphingolipids that specifically contain one or more sialic acid (N-acetylneuraminic acid; NANA) residues.

Biosynthesis and Degradation

Most animal glycosphingolipid families are derived from lactosylceramide (LacCer; β-D-galactosyl(1→4)-β-D-glucosyl-ceramide). The first step in lactosylceramide synthesis is the acylation and desaturation of D-erythro-sphinganine. The ceramide is then glucosylated on the cytosolic face of the endoplasmatic reticulum (ER) and Golgi membranes followed by β-galactosylation of glucosylceramide on the opposite face of the ER and Golgi membranes to form lactosylceramide. The glycan chain can be elongated by specific glycosyltransferases and sulfotransferases.

Glycosphingolipid biosynthesis, degradation, and intracellular transport are highly regulated, and cells demonstrate type-specific expression and stable glycosphingolipid patterns.

Functions

Glycosphingolipids are minor components of cell membranes and membrane compartments, and are connected to cell growth, differentiation, and viral and oncogenic transformations. Like GPI anchored proteins, glycosphingolipids aggregate to form membrane rafts on the micromembrane and the outer leaflet of the apical membrane. The hydrophobic lipid tail is embedded in the outer leaflet of cell membranes, positioning the glycan structure into the extracellular matrix. Gangliosides are the major constituents of neuronal cell membranes and the endoplasmic reticulum.

Glycosphingolipids are thought to provide protection from harsh conditions in the extracellular environment, such as low pH and degrading enzymes. They help cells to interact with extracellular matrices and other cells, and serve as surface receptors for bacterial toxins and possibly endogenous extracellular molecules. In addition to their function as membrane components, glycosphingolipids are precursors for lipids involved in signal transduction and contribute to the water permeability barrier of the skin. The skin and the brain are the key organs in which functional aspects of mammalian glycosphingolipids are important.

Galactosylceramide derivatives are necessary key components of myelin and have demonstrated growth factor-like properties. Acidic gangliosides influence the electrical field across the cellular membrane, as well as the concentration of ions on the external surface of the cells. In addition, gangliosides may have a role in electrical insulation in myelin cells in the nervous system.

Some gangliosides, such as those that contain the sialyl Lewis X (sLeX) structure (see Figure 1), are useful as cancer cell markers, since they are elevated in the membranes of certain types of tumor cells such as melanomas and metastatic brain tumors. Purified gangliosides are frequently used as markers for characterization of various cell types. They may also serve as substrates and inhibitors of glycosidases and glycosyltransferases.

Structure of the tetrasaccharide sialyl Lewis X

Figure 1. Structure of the tetrasaccharide sialyl Lewis X (sLex) attached to galactosylceramide (GalCer). Cer represents the ceramide moiety.

Gangliosides are named in accordance with the IUPAC Guidelines “Nomenclature of Glycolipids, IUPAC Recommendations 1997)”, Pure Appl. Chem., 69, 2475‑2487 (1997). The letter “G” is used to indicate ganglioside and the number of sialic acid residues are abbreviated as M (mono), D (di) or T (tri).

Materials

     

Reference

  1. International Union of Pure and Applied Chemistry (IUPAC) and International Union of Biochemistry and Molecular Biology (IUBMB) Joint Commission on Biochemical Nomenclature (JCBN) Nomenclature of Glycolipids, Recommendations (1997). http://www.chem.qmul.ac.uk/iupac/misc/glylp.html.

 

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