Phcoker
www.phcoker.com
How do Brain Ganglioside(GM1) Structures and Metabolism work? Gangliosides(GM1) are members of the larger glycosphingolipid family, consisting of glycans attached to a ceramide lipid . Ceramides are composed of a long-chain amino alcohol, sphingosine, with a C2 primary amine that is N-acylated with a long-chain fatty acid amide. Brain ganglioside ceramides typically have C1- and C3-hydroxyl groups and a C4-C5 double bond, with the C1-hydroxyl linked via glycosidic linkage to the glycan chain. The properties of sphingolipids are unusual due to the nature of their lipid moieties. The sphingosine chain of mammalian brain gangliosides is long (18 or 20 carbons), and the fatty acid amide is saturated (typically C18:0). This results in a relatively rigid structure within the plane of the outer leaflet of the plasma membrane, and thereby results in enhanced lateral self-association. Ganglioside-enriched domains may also be enriched in other sphingolipids (notably sphingomyelin), cholesterol, glycosylphosphatidylinositol-linked cell surface proteins, fatty acylated intracellular signaling proteins (e.g., Src family members), and selected transmembrane scaffold and/or signaling proteins. Together, these lateral associations within the plasma membrane have been called lipid rafts, glycolipid-enriched microdomains, or detergent-resistant membranes. For perspective, gangliosides constitute âˆź0.6% of total brain lipids, but are more highly enriched in neurons. The lipid composition of the whole brain is as follows (in Îźmol/g wet wt, adult rat): phosphoglycerolipids, 89; cholesterol, 69; galactosylceramides, 23; sphingomyelin, 7; gangliosides, 1.1. Gangliosides reside primarily in the outer leaflet of the plasma membrane, with the ceramide and much of the first sugar (glucose) engaged with the lipid leaflet, and the glycan extending out into the surrounding milieu. The dual properties of intraleaflet lipid associations and glycan extension outward from the membrane bilayer provide the ability of gangliosides to act as cell surface recognition and regulation molecules. 1
info@phcoker.com
Phcoker
www.phcoker.com
Although many ganglioside structures have been identified in a variety of tissues and organisms, adult mammalian brain gangliosides are dominated by just four closely related structures (GM1, GD1a, GD1b, and GT1b) that together represent the vast majority (97%) of gangliosides in the adult human brain. The same four structures comprise the major sialoglycans in the brains of all adult mammals and birds, indicating a selective advantage for expression of these particular structures. These four gangliosides share the same neutral glycan core (Gal β1–3 GalNAc β1–4 Gal β1–4 Glc β1–1 Cer) with varying numbers of sialic acids attached to the internal and terminal galactose residues. The four major brain gangliosides are synthesized stepwiseby glycosyltransferases that transfer each monosaccharide from its activated form (UDP-Glc, UDP-Gal, UDP-GalNAc, or CMP-NeuAc) to the growing glycan chain. A key branch point in the biosynthetic chain is GM3, which can be extended by addition of an α2–8-linked NeuAc to form GD3 or by a β1–4-linked GalNAc to form GM2. Once the GalNAc is transferred, internal α2–8-linked NeuAc residues cannot be added, dedicating this pathway to biosynthesis of GM1 and GD1a, so-called “a-series” gangliosides. GD3, in contrast, can be extended by addition of GalNAc and subsequent sugars to form GD1b and GT1b, “b-series” gangliosides. There are many less abundant gangliosides in the brain that may have important functions in physiology and pathology. Among these are the “0-series” gangliosides that arise from transfer of GalNAc to lactosylceramide (no Sia on the internal Gal), the “c-series” gangliosides (not shown) that have a trisialyl moiety (NeuAc α2–8 NeuAc α2–8 NeuAc α2–3) on the internal Gal. GQ1b carries a diSia moiety on the outermost Gal residue, whereas the rare “α-series” gangliosides carry an α2–6-linked Sia on the GalNAc residue (e.g., GD1α). Very rare gangliosides may carry up to seven total Sia residues, including linear oligomers of up to five sialic acids. Gangliosides bearing longer oligo- or polysialic acid chains have not been reported. Ganglioside catabolism occurs stepwise by the actions of glycan-specific exoglycosidases. Removal of specific terminal glycans must proceed prior to further ganglioside degradation. Mutations in specific ganglioside glycosidases result in 2
info@phcoker.com
Phcoker
www.phcoker.com
devastating lysosomal storage diseases. For example, mutation of the β-galactosidase gene GLB1 results in GM1 gangliosidosis, whereas mutation of either of the two genes coding the β-N-acetylhexosaminidase subunits (HEXA or HEXB) results in GM2 gangliosidosis.
3
info@phcoker.com