Animal Glycolipids

Abstract

Glycolipids are integral components of animal cell membranes, composed of a glycan covalently linked to a lipid. They include glycosphingolipids (GSLs) (ceramide‐linked), glycoglycerolipids (diacylglycerol‐ or alkylacylglycerol‐linked) and glycosylphosphatidylinositols (GPIs) (phosphatidylinositol‐linked). Their lipid components are embedded in a cell membrane with their glycans extending outwards where they interact with components in the plane of the same membrane or with glycan‐binding proteins, including soluble proteins and those on surfaces of other cells. Most animal glycolipids are GSLs, which can be as simple as ceramide monosaccharides or as large and complex as branched ceramide octadecasaccharides. Animal glycoglycerolipids are a simpler family, primarily galactose or sulphogalactose linked to glycerolipid. GPIs are glycans attached to the common membrane lipid phosphatidylinositol at one end and to a protein at the other, anchoring the protein to the membrane. Animal glycolipids serve diverse and essential functions in cell physiology in animals as simple as Caenorhabditis elegans and as complex as humans.

Key Concepts

  • Animal glycolipids are amphipathic molecules composed of a lipid embedded in a cell membrane and a glycan extending outwards.
  • Most animal glycolipids are glycosphingolipids (GSLs), glycans carried on a ceramide lipid core.
  • GSL glycans can be as simple as a single neutral sugar (glucosylceramide and galactosylceramide) or can be large, complex, branched and/or charged.
  • GSLs are categorised as neutral GSLs, sulphated GSLs or gangliosides (sialic acid containing GSLs).
  • Animal GSLs are named based on seven distinct neutral tetrasaccharide cores referred to as: ganglio‐, lacto‐, neolacto‐, globo‐, isoglobo‐, mollu‐ and arthro‐series.
  • Animal glycoglycerolipids include galactose and 3‐sulphogalactose bound to diacylglycerol or alkylacylglycerol. They are scarce except in testes, where they are the major glycolipids and are required for spermatogenesis.
  • Animal glycosylphosphatidylinositols (GPIs) consist of a core tetrasaccharide in glycosidic linkage to the inositol of phosphatidylinositol, a common membrane phospholipid.
  • Animal GPIs carry a distal ethanolamine group, the terminal amine of which is linked via amide linkage to a select group of proteins, anchoring them to the membrane.
  • Animal glycolipids tend to associate into functional microdomains in the plane of the membrane, often with sphingomyelin, cholesterol and select signalling proteins.
  • GSLs function by binding laterally to molecules in the same membrane to regulate their activities (cis regulation) or by acting as receptors for soluble or cell surface glycan binding proteins (trans recognition).

Keywords: plasma membrane; lipid raft; ganglioside; GPI anchor; glycan binding protein

Figure 1. Glycosphingolipids. Sphingosine is a long chain amino alcohol with the structure 1,3‐dihydroxy‐2‐amino‐octadecene in the d‐erythro stereoconfiguration. Fatty acids of various chain lengths (typically fully saturated) are linked to the 2‐amino group of sphingosine to form ceramide. Sugars are linked to the carbon 1 (C1) hydroxyl group of ceramide to form simple glycosphingolipids such as glucosylceramide or a wide variety of more complex structures including the sialic‐acid‐bearing glycosphingolipid ganglioside GT1b shown. Structural variability in the sphingosine chain length, saturation and hydroxylation, in the fatty acid length and in the glycan provide structural and functional diversity in glycosphingolipid structures across cells, tissues and organisms.
Figure 2. Comparison of major vertebrate galactosylceramides and galactosylglycerolipids. Glycoglycerolipids are typically much less abundant that glycosphingolipids. They are composed of sugar(s) linked to the free hydroxyl of diacylglycerol or alkylacylglycerol. In vertebrates, GalCer and 3‐sulpho‐GalCer (sulphatide) are major components in the brain, whereas the related galactosyldiacylglycerol is a minor species in some vertebrate brains, and 3‐O‐sulphated galactosylalkylacylglycerol (seminolipid) is a major glycolipid of vertebrate seminal plasma. In animals, glycoglycerolipid glycans are rarely more complex than those shown, whereas glycosphingolipids include large complex glycan structures.
Figure 3. A mammalian glycosylphosphatidylinositol (GPI) anchor. GPI anchors consist of phosphatidylinositol, often an alkylacylglycerol as shown, with the inositol 6‐carbon carrying a glycan composed of a glucosamine (free amine) and three mannoses, the last of which has a phosphoethanolamine at its 6‐carbon that is in amide linkage to the carboxy terminus of a protein, thereby anchoring the protein to the cell membrane. The inositol often carries an additional fatty acid ester, as shown, which enhances membrane association. Variations in the sugar chain, including additional phosphoethanolamine groups (as shown) and/or additional branching sugars, provide glycan diversity in GPI anchors.
Figure 4. Glycosphingolipid neutral cores and their designation based on IUPAC Nomenclature of Glycolipids. Symbol nomenclature is that of Varki et al. ().
Figure 5. Common lacto‐ and neolacto‐series GSLs.
Figure 6. Common globo‐series GSLs.
Figure 7. Major brain gangliosides of mammals and their biosynthesis. Genes (human) responsible for the expression of ganglioside biosynthetic enzymes are boxed.
Figure 8. Subcellular compartmentalisation of GSL biosynthesis. GSL metabolism is depicted in the context of membrane‐delimited compartments within the cell. Biosynthetic products are membrane constrained, starting on the cytoplasmic face of the endoplasmic reticulum (ER) and progressing via vesicular (GalCer) or protein‐bound (GlcCer) transport to the Golgi apparatus. Curved arrows indicate spontaneous (ceramide) or facilitated (GlcCer) translocation between the cytoplasmic and luminal membrane leaflets. Translocation of GlcCer to the luminal face (*) may occur after retrograde transport to the ER followed by vesicular transport to the Golgi (not shown). Subsequent biosynthesis occurs on the luminal side of the Golgi, which becomes the outer leaflet of the plasma membrane upon vesicular transport and membrane fusion. Endocytosis results in GSLs facing the lumen of endosomes and lysosomes, where they are catabolised.
Figure 9. Lactosylceramide is a central structure in most animal GSL biosynthesis. Biosynthetic pathways are shown leading from ceramide through GlcCer to LacCer, and then to five major classes of GSLs. Genes (human) responsible for LacCer extension are boxed. Note that once LacCer accepts a C4‐linked GalNAc, the resulting structure (Gg3Cer) is no longer an acceptor for C3‐linked sialylation, so the ganglio‐series GSLs branch from LacCer into multiple subseries (0‐, a‐, b‐ and c‐).
Figure 10. Atomic‐resolution conformational analysis of ganglioside GM3 in a lipid bilayer. The image represents a 20‐ns snapshot taken perpendicular to the plane of the bilayer near the head group of GM3. The ganglioside is shown as a ball‐and‐stick model and the membrane as a transparent space‐filling model with the membrane hydrophilic region in blue and membrane hydrophobic region in white. Reproduced with permission from DeMarco and Woods (2009) © Oxford University Press.
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Further Reading

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Schnaar, Ronald L(Sep 2015) Animal Glycolipids. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000706.pub3]