Lactosylceramide and non-Acidic Oligoglycosylceramides
Non-acidic (neutral) di- and oligoglycosphingolipids, i.e. with two or more carbohydrate moieties attached to a ceramide unit, are vital components of cellular membranes of most eukaryotic organisms and some bacteria. While lactosylceramide is the key intermediate in the biosynthesis of more highly glycosylated sphingolipids, it also has important functions in its own right. Oligoglycosphingolipids possess a high degree of diversity in their structures and are amphipathic molecules because of the presence of the variable hydrophilic carbohydrate-rich head group with a hydrophobic ceramide tail. Their abundance relative to other lipids is usually low other than in epithelial and neuronal cells, with the nature and proportions of the different glycolipid classes varying with the type of cell and the stage of growth. However, they are extremely important for the function of cells.
1. Lactosylceramide and Other Diosylceramides
The most important and abundant of the diosylceramides is β-D-galactosyl-(1-4)-β-D-glucosyl-(1-1')-ceramide (Galβ1-4Glcβ1Cer), more conveniently termed lactosylceramide (LacCer), using the trivial name of the disaccharide. In the early literature, it was termed 'cytolipin H'.
It is found in small amounts only in most animal tissues, but it has a number of significant biological functions and it is of great importance as the biosynthetic precursor of most of the neutral oligoglycosylceramides and the acidic sulfatides and gangliosides, discussed below and in separate web pages.
In animal tissues, the precursor glucosylceramide is transported by the sphingolipid transport protein FAPP2 to the distal Golgi, where it must first cross from the cytosolic side of the membrane possibly via the action of a flippase. Biosynthesis of lactosylceramide then involves addition of the second monosaccharides unit as its activated nucleotide derivative (UDP-galactose) to monoglucosylceramide on the lumenal side of the Golgi apparatus in a reaction catalysed by β‑1,4‑galactosyltransferases of which two are known. The lactosylceramide produced can be further glycosylated (see below), or it can be transferred to the plasma membrane mainly by a non-vesicular mechanism that is poorly understood, but it cannot be translocated back to the cytosolic leaflet. It is also regenerated by the catabolism of many of the lipids for which it is the biosynthetic precursor. Deletion of the lactosylceramide synthase by gene targeting is embryonically lethal.
Lactosylceramide may assist in stabilizing the plasma membrane and activating receptor molecules in the special micro-domains known as rafts, as with the oligoglycosylceramides (see below); very-long chain fatty acid constituents (24:0 and 24:1) are essential for this function. In particular, lactosylceramide forms raft micro-domains on the plasma membrane of neutrophils (where it amounts to 70% of the glycosphingolipids) and macrophages, which recognize, engulf and eliminate pathogens. In this environment, the lipid has its own specialized role in the innate immune system in that it is known to bind to many species of pathogenic bacteria and fungi by reacting with fungal-derived β-glucans and Mycobacteria-derived lipoarabinomannans via carbohydrate-carbohydrate interactions (like the oligoglycosylceramides below). Mechanistically, it acts as a pattern recognition receptor as it is able to detect pathogen-associated molecular patterns and then promote activation of phagocyte functions, such as chemotaxis, phagocytosis and superoxide generation, by binding to specific membrane enzymes (e.g. Src family kinase Lyn) and mediating the immune and inflammatory responses by stimulating the formation of microbiocidal molecules. Similarly, membrane microdomains enriched in lactosylceramide interact with other membrane proteins, such as growth factor receptors, and are important in regulating their physiological properties. Lactosylceramide may also participate in glycan-glycan interactions with gangliosides such as GM3.
In addition, it is believed that a number of pro-inflammatory factors activate lactosylceramide synthase to generate lactosylceramide, which in turn activates "oxygen-sensitive" signalling pathways that affect such processes as proliferation, adhesion, migration and angiogenesis, especially in aortic smooth muscle cells. Dysfunctions in these pathways can affect cancer and several diseases of the cardiovascular system, while inflammatory states, especially those involving neural damage such as multiple sclerosis, are also affected. Lactosylceramide is reported to enhance the migration of monocytes with effects upon atherothrombosis. In consequence, the metabolism of this lipid is a potential target for new therapeutic treatments.
Lactosylsphingosine, i.e. the deacylated or lyso form, occurs naturally at low levels in brain where it may have some unspecified function.
Other diglycosylceramides: Galabiosylceramide (Galα1→Galβ1-1'Cer) has been found in small amounts in kidney, pancreas and cerebrospinal fluid, and it is one of the lipids that accumulates in excessive amounts in Fabry's disease (see below). It is the precursor of the minor 'gala' series of oligoglycosylceramides. Other diosylceramides containing mannose units may be present in some primitive animal species and in plants. In addition, several insect species contain mannose linked to glucosylceramide (βMan(1→4)Glc), while a starfish has been found to contain gentiobiosyl- and cellobiosylceramide as well as lactosylceramide; other marine invertebrates contain melibiosylceramides. In the model marine diatom, Thalassiosira pseudonana, under phosphate deprivation, a novel diglycosylceramide replaces phosphatidylcholine in part.
2. Non-Acidic Oligoglycosylceramides of Animal Tissues
Neutral oligoglycosylceramides with from three to more than twenty monosaccharide units in the chain have been detected in animal tissues ('megaloglycolipids' with up to 50 carbohydrate groups occur in erythrocytes). Of these, tri- to pentaglycosylceramides are often the most abundant or at least are the most intensively studied. As of 2009, 172 such oligoglycosylceramides with variations in the carbohydrate chain had been characterized in vertebrates alone.
Seven main and several minor series of oligoglycosylceramides are recognized from structural and biosynthetic relationships. As the systematic names tend to become rather cumbersome, semi-systematic names are usually recommended in which trivial names for a "root" structures are used as a prefix. The recommended root names and structures are listed in Table 1. In each instance, the primary unit linked to ceramide is glucose (Glc), with galactose (Gal), N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc) or mannose (Man) as the other monosaccharides units.
Table 1. Root names and structures of the main series of oligoglycolipids
|Roota||Symbol||Root structure||Trivial name|
a There are also minor isoganglio-, lactoganglio-, neogala-, schisto- and spirometo-series
b In this instance, 'lacto' does not refer to lactose
c The prefix 'neo' is used here to denote a (1→4) vs (1→3) difference in the linkage position between the monosaccharide units IV and III.
d The prefix 'iso' is used here to denote a (1→3) vs (1→4) difference in the linkage position between the monosaccharide units III and II.
The name of a given glycosphingolipid is then composed of (root name)(root size)osylceramide. Thus, lactotetraosylceramide or LcOse4Cer designates the second structure listed in Table 1 linked to a ceramide. When it is necessary to refer to specific glycose residues, Roman numerals are used, counting from that nearest the ceramide (i.e. I to IV in this example). As further monosaccharides units are added to or substituted for these basic structures, or when branches occur, the nomenclature becomes increasingly complex, and this would take us into the realm of the specialist. The IUPAC-IUB recommendations cited below should then be consulted.
Fucolipids are oligoglycolipids in any of the above series in which a fucose (Fuc) residue substitutes for one or more of the usual carbohydrate residues, but most often the terminal one. In addition, certain of the oligoglycolipids exist as lipid sulfates, and others are linked to sialic acid residues, i.e. the gangliosides.
Many different neutral oligoglycosphingolipids are present in various organs and species of animals, with further complexity being added by the nature of the ceramide unit. Invertebrates, especially those of marine origin, tend to have very different sphingolipid compositions from those in higher animals. In any given cell type, the number of different glycosylceramides may be relatively small, but their nature and compositions may be characteristic and in some way related to their function in the cell. This composition tends to change substantially as an animal develops. Comprehensive descriptions of all the innumerable complex oligoglycosylceramides are impossible here, and a few selected examples of particular biological importance are discussed below.
Often with these sphingoglycolipids, it has been the nature of the carbohydrate moiety that has received most study, as this is usually presumed to carry the primary biochemical function. That said, it is apparent that the ceramide component of oligoglycosylceramides is important for their proper function or optimum performance in membranes. Data on the nature of the fatty acid and long-chain base constituents are relatively sparse, but in general it appears that these tend to reflect their biosynthetic origins and resemble those of the precursor glucosylceramides. In general, as might be expected, the fatty acids are long-chain saturated and monoenoic in nature, but an exception is in the testicular lipids where there are distinctive fucolipids containing polyunsaturated fatty acids; these lipids appear to be essential for spermatogenesis and fertility in male mice.
3. Biosynthesis and Function of Oligoglycosphingolipids in Animals
The pathways for the biosynthesis of neutral oligoglycosphingolipids are illustrated. Glucosyl- and galactosylceramide synthesised on the cytosolic side of the endoplasmic reticulum and early Golgi membranes are transferred to the luminal side of the Golgi via the trans-Golgi by the sphingolipid transfer protein FAPP2. Further glycosylation occurs through the activity of a variety of distinct glycosyltransferases with differing substrate specificities, some of which appear to recognize only the carbohydrate portion of the molecule while others respond to the nature of the ceramide backbone. Nucleotide sugars, e.g. UDP-Glc, UDP-Gal, etc., are utilized as donor substrates for the transfer of sugar residues and are synthesised in the cytoplasm. The glycosyltransferases have at least one predicted nucleotide binding domain and invert the anomeric configuration of the nucleotide donor substrate in the reaction product. These act as part of a complex but highly structured organization of enzymes in the Golgi that includes membrane-bound sugar transporters and donor sugar nucleotides. This enzyme complex directs the synthetic steps that determine which series of glycolipids are formed by adding the appropriate monosaccharides sequentially to the non-reducing end of the growing carbohydrate chain.
In the most important pathway, the first step is the synthesis of lactosylceramide catalysed by galactosyltransferase I (discussed above), and this is the main metabolic branch point for the formation of the different classes of complex glycosphingolipids in mammals. Eventually the oligoglycosylceramide products are transported to the plasma membrane, where the carbohydrate head group of glycosphingolipids can undergo some further modification by glyco-hydrolases and transferases.
Thus with lactosylceramide as the precursor, a β-1,4-N-acetylgalactosylaminyltransferase yields GA2, the α-2,3-sialyltransferase yields GM3, the α‑1,4‑galactosyltransferase yields Gb3, and the β-1,3-N-acetylglucosaminyltransferase yields Lc3. In turn, GA2, GM3, Gb3 and Lc3 are the precursors for the biosynthesis of the asialo, ganglio, globo/iso-globo and lacto/neo-lacto series of oligoglycosphingolipids, respectively, by addition of the appropriate monosaccharides. In addition to the formation of the minor gala series oligoglycosphingolipids, galactosylceramide can be sialylated to produce GM4 ganglioside or sulfated to produce sulfogalactolipids. The nature of the products is dependent upon the organizational topology of the multi-enzyme complexes and the availability of the required precursors, but further regulatory factors must be involved.
The structure of the carbohydrate component is critical for many of the functions of oligoglycosphingolipids, 80-90% of which occur on the plasma membrane exclusively facing into the extra-cellular space, providing it with a protective carbohydrate coating that is energetically inexpensive. The globo series glycolipids may be especially important in this context. By interacting with components of the signal transduction machinery such as hormones and receptors, glycosphingolipids regulate cellular signalling pathways by various means including controlling protein conformation, regulation of protein multimerization, and protein segregation to membrane domains, which may involve the placement of signalling molecules next to their effectors, i.e. the specific region of membranes known as 'rafts'. For example, trafficking of the main apical glycosphingolipid in many animal species, the Forssman glycolipid, from the Golgi apparatus to the apical surface of epithelial cells requires its interaction with the apically secreted protein galectin-9 to facilitate the delivery of both lipid and proteins into membrane raft domains.
On the other hand, there is an increasing body of evidence to suggest that the composition of the ceramide unit as well as that of the carbohydrate is important biologically. At the very least, the composition of the ceramide unit ensures that the lipid takes its correct place in the plasma membrane, with the hydroxy fatty acid constituents providing an additional and apparently essential hydrogen bonding capacity. Similarly, binding of various bacteria, viruses and antibodies to glycolipids seems to require specific ceramide compositions, often requiring the presence of hydroxy fatty acids, for example.
In developing mouse embryos, the globo and extended globo series of glycosphingolipids are the first to appear followed by those of the neolacto and lacto series. In humans, glycans containing the Galα4Gal structure have been found only in glycosphingolipids and not in glycoproteins, suggesting a special position of the globo series glycosphingolipids in human physiology.
The triose Gb3 or GbOse3Cer is a significant component of human erythrocytes, and this structure is the inner core of all globo-series oligoglycosylceramides (Table 2). It binds specifically to the verotoxins of Escherichia coli and to Shiga-like verotoxins; indeed it is an important factor in the progression of disease by facilitating entry into cells. While deletion of the Gb3 synthase by gene targeting in animal models does not produce any obvious phenotype, it does protect against the effects of these toxins. Once more, species containing very-long chain fatty acid components (24:0 and 24:1) are essential for this function by enabling raft formation. Studies with the bacterium Pseudomonas aeruginosa have shown that Gb3 in the plasma membrane interacts with lectins on the bacterial surface to trigger bending of the plasma membrane and complete engulfment of the bacterium. This globotriaosylceramide has also been implicated with other glycosphingolipids in host cell interactions with the human immunodeficiency virus (HIV), where it appears to be protective, but globotetraosylceramide (Gb4) facilitates the entry of the parvovirus B19 virus into cells. However, together with certain gangliosides, the concentration of Gb3 is elevated in a number of cancers, and it is associated with an increase of multidrug resistance.
Table 2. Structures of some important oligoglycosylceramides of the globo-series
Further, Gb3 globoside is an important factor in apoptosis by interaction with the Fas (CD95) receptor, sometimes termed the 'death receptor', which bears a characteristic domain that interacts specifically with Gb3 and lactosylceramide but not with Gb4 or gangliosides. This defines its internalization route, as well as the signalling outcome, as when paired to Gb3 this receptor is internalized by clathrin-dependent endocytosis, resulting in the transduction of a cell death signal derived from activation of the caspase-8 cascade.
The hexasaccharide globoside designated Globo-H, first observed in a breast cancer cell line, has been associated with a number of other cancers including those of the prostate, lung, colon, liver, ovary and uterus. Antibodies to Globo-H have been produced and have reached the phase III stage in clinical trials against triple negative breast cancer.
Isoglobotriaosylceramide (iso-Gb3 or iGb3), differing in the terminal glycosidic linkage, is a stimulatory antigen to Natural Killer T cells in vitro, suggesting that it is involved in controlling the responses of these cells to infections, malignancy, and autoimmunity in mice at least, although there are doubts as to whether it functions similarly in humans in vivo. The first triose in the lacto category, Lc3 (GlcNAcβ1-3Galβ1-4Glcβ1Cer), is important for embryonic development especially in the brain.
Among many vital functions, glycosphingolipids are important components of the body's immune defence system, either in haptenic reactivity or in antibody-producing potency, i.e. as cellular immunogens or antigens. Certain glycolipids are involved in the antigenicity of blood group determinants, while others bind to specific toxins or bacteria. For example, Propionibacterium, which causes a disease of the skin, binds to the lactosyl moiety of glycosphingolipids, as does the organism responsible for gonorrhea. Some glycosphingolipids function as receptors for cellular recognition, and they can be specific for particular tissues or tumours. Antibodies to specific glycolipids have been implicated in certain diseases of the autoimmune system. In addition, glycosphingolipids can modify the activity of membrane receptors, such as those for insulin, and epidermal and nerve growth factors. The main glycosphingolipid found in human erythrocytes is a tetrahexoside (GalNAcβ1-3Galα1-4Galβ1-4Glcβ-Cer), often abbreviated to Gb4Cer or GbOse4Cer, which was termed ‘globoside’ (as it was first obtained as a globular, birefringent precipitate and gave the root name to the globo-series).
The oligoglycosylceramides of erythrocytes have attracted particular interest, as they are important for cellular interactions including blood-type determinants, which are factors in deciding the suitability of blood and other tissues for transplantation. Gb3Cer and Gb4Cer constitute the basis of the blood group system. For example, the blood group O antigen is derived from Gb4Cer by addition of a fucose unit to the terminal galactose in α1,2‑linkage; the A antigen has a further N-acetylgalactosamine added, while in the B antigen the new terminal unit is galactose as illustrated.
Gb5Cer is a pentaosyl-ceramide of the globo-series and is a cell-surface markers used to define human embryonic stem cells. The Forssman antigen (GbOse5Cer with an additional terminal α-N-acetylgalactosamine) is of special interest in that it is species specific. Some animals (e.g. horse, cat, dog) are Forssman-positive and others (e.g. rat, pig) are Forssman-negative and lack the glycolipid. Although humans have been considered to belong to the latter group, certain populations have been found with this glycolipid in the intestinal mucosa. In addition, there are further globo-series glycolipids with various alternative carbohydrate moieties attached to the terminal GalNAc of Gb4, which have been isolated from human embryonic carcinoma and are believed to be functionally involved in the development of stem cells. Cats, dogs and horses contain a glycolipid similar to globosides but with sialic acid replacing the galactosamine; this has been termed ‘hematoside’. However, gangliosides based on the globo- and lacto-root structure in general are discussed elsewhere on this site.
Oligoglycosylceramides of the neolacto-series contain alternating residues of 1,3-substituted galactose and 1,4-substituted N-acetylglucosamine, i.e. N-acetyllactosamine units. At least 15 types are known with both linear and branched structures and they can be are heavily substituted with fucose moieties. In addition, there are some less well-characterized forms that contain up to fifty carbohydrate groups. They are especially important in that they are associated with blood groups A, B, H and other activities. Most of these lipids function as antigens, and some are associated with specific carcinomas. For example, a terminal N-acetylgalactosamine residue is essential for group A activity. Some of these lipids have distinctive ceramide structures including phytosphingosine and hydroxy acids.
Mucolipids, i.e. oligoglycosylceramides with di- to hexagalactosyl glycosides (some with branch structures) linked to glucosylceramide, are found predominantly in the gastrointestinal mucosa. The neutral oligoglycosylceramides are vital protective components of the membranes of the brush border of intestinal cells, where much of the digestion and absorption of nutrients occurs. Many of the main enzymes are localized in membrane rafts with little cholesterol but high concentrations of glucosylceramide and oligoglycosylceramides, such as lactosylceramide, globotriaosylceramide and ganglioside GM3, which are resistant to pancreatic enzymes, bile salts and the products of digestion. Surprisingly, phytosphingosine accounts for 70% of the sphingoid bases, and a high proportion of the fatty acids are hydroxylated in this instance. Pathogenic microorganisms, such as Helicobacter pylori, may be present in the digestive tract with the potential to enter the host system if the protective barrier of mucin and glycosphingolipids is damaged. In addition, within the host, organisms such as Streptococcus pneumonia have the capacity to hydrolyse membrane glycolipids and so increase the virulence of an infection.
Mannosylglucosylceramide (Manβ1-4Glcβ1-cer) is the precursor diosylceramide for the complex glycosphingolipids in Drosophila, widely studied as an insect model. N-Acetylgalactosamine residues are then added sequentially, the first via a β1-3 linkage and subsequently via β1-4 linkages (up to eight carbohydrate residues, some linked to phosphoethanolamine units). In this instance, the long-chain bases tend to be C14 and C16 in chain-length.
Parasitic nematodes contain distinctive zwitterionic oligoglycosphingolipids of the arthro series with phosphocholine moieties attached as highly conserved, antigenic glycolipid markers. The glycosphingolipids of the pig parasitic nematode, Ascaris suum, have been most studied, and they are characterized by the phosphodiester-bound phosphocholine substituent linked to C6 of a central N-acetylglucosamine residue. In addition, some of these glycosphingolipids carry phosphorylethanolamine linked to C6 of an adjacent mannose residue. The ceramide moiety contains (R)-2-hydroxytetracosanoic acid as the main fatty acid component and C17 iso-branched sphingosine and sphinganine bases.
4. Oligoglycosylceramides of Plants and Microorganisms
In plants and fungi, elongation of glucosylceramide, not galactosylceramide, occurs to form two series of oligoglycosylceramides with either mannosyl or galactosyl units by mechanisms that are presumably related to those in animals. In the mannosyl series in higher plants, up to four mannosyl units may be added via β1→4 linkages. In a second series, addition of a 1-4 linked β‑D‑glucopyranosyl unit terminates the elongation step after 1, 2 or 3 mannose units have been coupled together. This results in a series of di-, tri-, tetra- and pentaglycosylceramides, terminating in either a glucose or mannose unit. These complex lipids are found mainly as constituents of the endoplasmic reticulum, Golgi, tonoplasts and plasma membrane, but little is known of their functions in plants.
A further series of oligoglycolipids found in algae and fungi involves linkage of up to three D-galactopyranosyl residues to the primary glucosylceramide unit, although not all members of the series have been characterized in a single organism.
The fatty acid and sphingoid base compositions tend to reflect their biosynthetic origins and resemble those of the precursor monoglycosylceramides. Although some species differences are found, the fatty acids are mainly saturated 2-D-hydroxy acids with 14 to 26 carbon atoms. Phytosphingosines (including 8-cis/trans isomers) and various 4t,8c/t-sphingadienes are the main long-chain bases.
A tetraglycosylceramide has been isolated from the mould Neurospora crassa, while the bacterial genus Sphingomonas also contains a tetraglycosylceramide α‑D‑Manp(l→2)-α-D-Galp-(1→6)-α-D-GlcpN-(1→4)-α-D-Glcpα(1→1)Cer, i.e. with an α- rather than a β-linkage to the ceramide unit, in addition to a cerebroside analogue. While monoglycosylceramides are frequently reported from fungi and yeasts, complex lipopolysaccharides and glycosylinositol phosphorylceramides appear to take the place of neutral oligoglycosylceramides.
5. Catabolism of Non-Acidic Oligoglycosylceramides in Animals
As discussed in the web page dealing with monoglycosylceramides, oligoglycosphingolipids are degraded in lysosomal compartments within the cell by water-soluble hydrolases, aided by various activator proteins termed saposins and by anionic lipids such as bis(monoacylglycero)phosphate, which is enriched in lysosomal membranes. In brief, sections of plasma membrane containing glycosphingolipids intended for degradation are endocytosed and transported to the lysosomes where exohydrolases cleave sugar residues sequentially from the non-reducing end. The cleaved fragments, i.e. the sugar residues and ceramide, with the latter often hydrolysed subsequently to fatty acids and sphingoid bases, can then leave the lysosomes and be degraded further or re-enter the biosynthetic pathways.
An alternative catabolic pathway in certain bacteria and leeches involves the action of a ceramide glycanase to cleave the β-glucosidic linkage between glucose and ceramide, which results in the formation of ceramide and an oligosaccharide. This enzyme has proved of value in the structural analysis of glycosphingolipids.
Fabry's disease: If any of the ten different hydrolase enzymes is deficient in animal tissues, the corresponding lipid substrate accumulates and is stored in the lysosomal compartment, sometimes to a considerable extent as in the inherited sphingolipid storage pathologies such as Fabry's disease, a genetic disorder (X‑linked) arising from the absence of the lysosomal enzyme α-galactosidase A, which catalyses the hydrolytic cleavage of the terminal galactose unit. This leads to deposition of excessive amounts of glycosphingolipids with terminal galactose units, such as globotriaosylceramide (Gb3), galabiosylceramide and lactosylceramide in tissues, especially in the kidney, heart and brain. The presence of globotriaosylceramide in urine or its lyso (non-acylated) form in serum are aids to diagnosis. Globotriaosylsphingosine (lyso-Gb3) can also accumulate to high levels in vasoendothelial cells and has a role in nephropathy and secondary inflammatory events. Enzyme replacement therapy is now making a significant contribution to ameliorating the affects of the disease.
High-performance thin-layer chromatography is widely used for separation of various types of oligoglycolipids, based on the number and to some extent the type of monosaccharide units, though high-performance liquid chromatography (sometimes after benzoylation) is also employed for the purpose. Mass spectrometry is the main method for identifying and sequencing the carbohydrate chains, with invaluable assistance from nuclear magnetic resonance spectroscopy. Indeed, modern mass spectrometric methods, especially with electrospray ionization and matrix-assisted laser desorption/ionization (MALDI), appear to have greatly eased the technical problems of structural analysis.
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Updated: October 6th, 2021
|Author: William W. Christie|