The glycosphingolipids differ from sphingomyelin in that they do not contain phosphate, and the polar head function is provided by a monosaccharide or oligosaccharide attached directly to the ceramide by an O-glycosidic bond (Fig. 17.14). The number and type of carbohydrate moieties present determine the type of glycosphingolipid.
A. Neutral glycosphingolipids
The simplest neutral glycosphingolipids are the cerebrosides. These are ceramide monosaccharides that contain either a molecule of galactose (forming ceramide-galactose or galactocerebroside, the most common cerebroside found in myelin, as shown in Fig. 17.14) or glucose (forming ceramide-glucose or glucocerebroside, an intermediate in the synthesis and degradation of the more complex glycosphingolipids). [Note: Members of a group of galacto-or glucocerebrosides may also differ from each other in the type of FA attached to the sphingosine.] As their name implies, cerebrosides are found predominantly in the brain and peripheral nerves, with high concentrations in the myelin sheath. Ceramide oligosaccharides (or globosides) are produced by attaching additional monosaccharides to a glucocerebroside, for example, ceramide-glucose-galactose (also known as lactosylceramide). The additional monosaccharides can include substituted sugars such as N-acetylgalactosamine.
B. Acidic glycosphingolipids
Acidic glycosphingolipids are negatively charged at physiologic pH. The negative charge is provided by N-acetylneuraminic acid ([NANA], a sialic acid, as shown in Fig. 17.15) in gangliosides or by sulfate groups in sulfatides.
1.
Gangliosides: These are the most complex glycosphingolipids and are found primarily in the ganglion cells of the CNS, particularly at the nerve endings. They are derivatives of ceramide oligosaccharides and contain one or more molecules of NANA (from CMP-NANA). The notation for these compounds is G (for ganglioside) plus a subscript M, D, T, or Q to indicate whether there is one (mono), two (di), three (tri), or four (quatro) molecules of NANA in the ganglioside, respectively. Additional numbers and letters in the subscript designate the monomeric sequence of the carbohydrate attached to the ceramide. (See Fig. 17.15 for the structure of GM2.) Gangliosides are of medical interest because several lipid storage disorders involve the accumulation of NANA-containing glycosphingolipids in cells (see Fig. 17.20, p. 212).
2.
Sulfatides: These sulfoglycosphingolipids are sulfated galactocerebrosides that are negatively charged at physiologic pH. Sulfatides are found predominantly in the brain and kidneys.
VII. GLYCOSPHINGOLIPID SYNTHESIS AND DEGRADATION
Synthesis of glycosphingolipids occurs primarily in the Golgi by sequential addition of glycosyl monomers transferred from UDP-sugar donors to the acceptor molecule. The mechanism is similar to that used in glycoprotein synthesis (see p. 166).
A. Enzymes involved in synthesis
The enzymes involved in the synthesis of glycosphingolipids are glycosyltransferases that are specific for the type and location of the glycosidic bond formed. [Note: These enzymes can recognize both glycosphingolipids and glycoproteins as substrates.]
B. Sulfate group addition