By: Richard D. Cummings
Glycosphingolipids (GSLs) are sphingolipids, such as ceramide, to which sugars are linked. They are found in virtually all organisms including bacteria, fungi, plants, and animals (1), and many different human and animal parasites (2). Sphingolipids were originally discovered by Johann Ludwig Wilhelm Thudichum in 1884 in studies on the chemical makeup of the brain (3,4), and because of their near mystical natures, the compound was given the name sphingosine after the sphinx in Greek mythology (5). Thudichum also used the term cerebroside to denote sphingolipids with sugars in the brain, a kind of analogy to those recently discovered plant glycosides, and believed the ceramide to have a sugar which he termed cerebrose.
Two of the smallest glycolipids commonly found in animals are glucosylceramide (GlcCer - Glcβ1-Cer) and galactosylceramide (GalCer - Galβ1-Cer)(6), which are termed glycosphingolipids (GSLs) (6). They are mainly found in animals, plants and fungi. Interestingly, some bacteria, such as Sphingomonas capsulata, make related glycosylceramides, which appears to lack lipopolysaccharides and instead generate glycosphingolipids that include the unusual GlcAα1-Cer and Galα1-6GlcNα1-4GlcAα1-Cer (7).
GlcCer is essential for normal development in organisms that express it, as shown in multiple studies, such as those in Caenorhabditis elegans, plants, and mice (8-10). GlcCer is typically elongated in animals to very complex GSLs, including all the gangliosides (1). The synthesis of GlcCer requires the enzyme glucosylceramide synthase; orthologs of the gene encoding this enzyme are present in animals, yeast/fungi, plants and even bacteria (11).
GalCer is an isomer of GlcCer but has completely different functions and biosynthetic pathways. GalCer is also the precursor to sulfatide (3-O-sulfated GalCer). Unlike GlcCer, GalCer is not typically elongated with additional sugars. The term sulfatide, which was also coined by Thudichum (12), is rather general, as sulfated lactosylceramide (3-O-sulfated-Gal-Glc-Cer) is also termed a sulfatide. A related glycolipid is seminolipid, 3-O-sulfo monogalactosylalkylacyl-glycerol, which is not a glycosphingolipid; it is synthesized using alkylacylglycerol as a donor and modified by the same galactosyltransferase and sulfotransferase that synthesize sulfatide. The unusual seminolipid is synthesized by spermatocytes and is required for spermatogenesis (13).
Both GalCer, largely as sulfatide, and galactosylsphingosine (psychosine) are highly expressed in the brain (12). Krabbe disease, a heritable lysosomal storage disorder, is due to an inability to degrade GalCer in lysosomes, due to defective expression of galactosylceramidase (GALC), resulting in accumulation of GalCer. This accumulation is most noteworthy in oligodendrocytes (central nervous system) and Schwann cells (peripheral nervous system). An interesting study in which doubly-deficient mice were generated lacking the enzymes for GalCer synthesis and degradation, led to interesting neuronal phenotypes along with sterility of male mice (14). It is also interesting that male mice lacking GalCer galactosyltransferase and unable to synthesize either GalCer or sulfatide are infertile (15). Sulfatide levels are also typically tightly controlled. A disorder named Metachromatic Leukodystrophy (MLD) is caused by elevated levels of sulfatide (16), which can arise by a deficiency of Arylsulfatase A. This can lead to progressive loss of myelin.
The biosynthesis of GlcCer occurs at the ER membrane on its cytoplasmic-facing side by the enzyme GlcCer synthetase; it uses cytoplasmic UDP-Glc as the donor and the resultant GlcCer is then ‘flipped’ into the ER lumen (6,17,18). However, while it was thought earlier that GalCer was synthesized in the Golgi, it is actually synthesized within the ER lumen by GalCer galactosyltransferase. The UDP-Gal used by the enzyme is imported into the ER and thus, no flipping is required for GalCer (19). Interestingly, GlcCer is also the donor for the synthesis of glucosyl-cholesterol, which is generated by a transglycosylation reaction catalyzed by the lysosomal glucocerebrosidase (GBA) (20).
A useful drug to block synthesis of GlcCer in cells by inhibiting glucosylceramide synthesis is PDMP (1-phenyl-2- decanoylamino-3-morpholino-1-propanol) (21). This and related drugs have been incredibly useful in studying the roles of glycosphingolipids in cellular functions (22).
References
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