International Scholarly Research Network ISRN Biochemistry Volume 2012, Article ID 506160, 36 pages doi:10.5402/2012/506160 Review Article Ganglioside Biochemistry Thomas Kolter Program Unit Membrane Biology & Lipid Biochemistry, LiMES, University of Bonn, Gerhard-Domagk Straße 1, 53121 Bonn, Germany Correspondence should be addressed to Thomas Kolter, [email protected] Received 18 September 2012; Accepted 9 October 2012 Academic Editors: H. Itoh and B. Penke Copyright © 2012 Thomas Kolter. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gangliosides are sialic acid-containing glycosphingolipids. They occur especially on the cellular surfaces of neuronal cells, where they form a complex pattern, but are also found in many other cell types. The paper provides a general overview on their structures, occurrence, and metabolism. Key functional, biochemical, and pathobiochemical aspects are summarized. 1. Introduction 2. Structure and Nomenclature Together with glycoproteins and glycosaminoglycans, gly- In their structures, gangliosides combine a glycan and a lipid cosphingolipids (GSLs) contribute to the glycocalyx that portion and contribute to both, the cellular lipidome and covers eukaryotic cell surfaces. Gangliosides are sialic acid- the glycome/sialome [15]. A great variety of carbohydrate containing glycosphingolipids and provide a significant part sequences are found within the GSLs [16], including the of cell surface glycans on neuronal cells. GSLs are lipids gangliosides [17]. Although carbohydrate residues of dif- that contain a sphingoid base and one or more sugar ferent structure, linkage, and anomeric configuration occur residues [1]. Sialic acids (Figure 1) are nine-carbon sugars in GSLs, only a limited number of the so-called series biosynthetically formed from N-acetylmannosamine and with characteristic carbohydrate sequences are found within phosphoenolpyruvate [2, 3]. With a mean pKA value of evolutionary related organisms (Table 1). Within the gan- around 2.6, they are more acidic than the majority of gliosides, sialic acids can be attached only to a few of the GSL carboxylic acids and negatively charged at most physiological series, in adult mammals especially to the ganglio series. pH values. The name “ganglioside” was coined by the Among the sialic acids, N-acetylneuraminic acid is the German biochemist Klenk (1896–1971) and assigned to a most frequently found member in humans, but also N- group of acidic GSLs that he isolated from ganglion cells glycolylneuraminic acid is abundant in many other species [4, 5] and from the brains of patients who suffered from (Figure 1). A total of more than 50 different sialic acids the so-called amaurotic idiocy [6, 7]. Sialic acid was first have been described [18, 19]. They can be O-acetylated isolated from submaxillary mucin in 1936 [8]. Its structure in positions 4, 7, or 9 [20], but also N-deacetylated, O- was elucidated in the nineteen fifties by different groups and methylated, sulfated, or modified by lactonization [21] (see it was found to be identical to that of the N-acetylneuraminic Figure 8). acid isolated by Klenk and Faillard. The first structure of a ThenomenclatureofGSLsspecifiestheglycanpart ganglioside was elucidated in 1963 by Kuhn and Wiegandt of these lipids. Two ganglioside nomenclature systems are [9]. In 1962, Svennerholm suggested a nomenclature of brain currently in use to assign names to the corresponding struc- gangliosides [10, 11]. The biochemical defects underlying tures. Most researches prefer the short-hand nomenclature the diseases formerly known as amaurotic idiocy, GM1- according to Svennerholm, which was initially based on gangliosidosis [12], Tay-Sachs- [13], and Sandhoff disease the migration order of ganglio-series gangliosides in chro- [14] were identified by Sandhoff and others in the 1960s. matography [10]. Later on, it has been extended to other 2 ISRN Biochemistry OH HOOC OH HOOC HO O OH HO O OH HN H3C HN HO HO HO HO HO O O N-acetyl-α-neuraminic acid N-glycolyl-α-neuraminic acid (Neu5Ac) (Neu5Gc) Figure 1: Sialic acids. Table 1: GSL series. and GD1c have a “b” and “c” in their names, although Series Core structure both are 0-series gangliosides (see the scheme of ganglioside biosynthesis, Figure 12). GM4 is a gala-series ganglioside, Arthro GlcNAcβ1,3Manβ1,4Glcβ1,1Cer although the “G” suggests ganglio series. Figure 2 shows the α β Gala Gal 1,4Gal 1,1 Cer structure of ganglioside GQ1b, one of the most abundant β β β Neogala Gal 1,6Gal 1,6Gal 1,1 Cer gangliosides in adult human brain (G = ganglio series, Q = 4 Ganglio Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1 Cer sialic acids, 5 − 1 = 4neutralcarbohydrateresidues,andb- Globo GalNAcβ1,3Galα1,4Galβ1,4Glcβ1,1Cer series = 2 sialic acids attached to the “inner” galactose). Isoglobo GalNAcβ1,3Galα1,3Galβ1,4Glcβ1,1Cer Ganglioside core structures can be additionally modi- Lacto Galβ1,3GlcNAcβ1,3Galβ1,4Glcβ1,1Cer fied; they can be elongated, such as in GD1aGalNAc [25] Neolacto Galβ1,4GlcNAcβ1,3Galβ1,4Glcβ1,1Cer (Figure 3). This ganglioside occurs, for example, on spinal Muco Galβ1,3Galβ1,4Galβ1,4Glcβ1,1Cer neurons [26, 27] and can give rise to autoantibodies as a Mollu Fucα1,4GlcNAcβ1,2Manα1,3Manβ1,4Glcβ1,1Cer cause of variant forms of the Guillain-Barre´ syndrome [28, 29] and other neuropathies [30]. A modified GM2 derivative Schisto GalNAcβ1,4Glcβ1,1Cer that contains taurine in amide linkage to the sialic acid car- β β β Spirometo Gal 1,4Glc 1,3Gal 1,1 Cer boxyl group has been identified in the brain of patients with Tay-Sachs disease [31]. Hybrid-type GSLs and gangliosides with postglycosylation modifications add further complexity root structures. The more comprehensive IUPAC system to this substance class [32]. As an example, lacto-ganglio [22] is less frequently applied. According to Svennerholm, hybrid-type gangliosides have been identified in bovine brain a core structure of neutral sugars define the name of [33]. a respective series, in which the pyranose forms of D- Most gangliosides found in adult mammals belong to the galactose (Gal), D-N-Acetyl-glucosamine (GlcNAc), or D- ganglio, gala, lacto, and neolacto series. Ganglioside GM4 N-Acetylgalactosamine (GalNAc) are attached in defined (Figure 3), a member of the gala series, has the structure order and linkage to lactosylceramide (Galβ1,4Glcβ1Cer) NeuAcα2,3Galβ1Cer and is often found with an α-hydroxy- or β-galactosylceramide (Galβ1Cer). The names contain fatty acid within the ceramide moiety. During development, information about the series (“G” = ganglio, “L” = lacto), also gangliosides with other core structures are transiently the number of sialic acids (“A” = 0, “M” =1, “D” = 2, “T” = formed, such as the stage-specific embryonic antigen SSEA- 3, “Q” = 4, “P” = 5, “H” = 6, “S” = 7), and, indirectly, 4, a ganglioside of the globo series [34](Figure 4). In adults, on the number of uncharged carbohydrates: initially it has globo-series gangliosides occur on human erythrocytes [35], been assumed that this number cannot exceed 5, so that in human kidney [36], and on various stem cells [37]. For the name “ganglioside GM1” indicates that this ganglioside example, SSEA-4, but not SSEA-3 or Globo-H (Figure 4), contains (5 − “1” = 4) neutral sugars of the ganglio series. is expressed in cord blood-derived mesenchymal stem cells This series is defined by the sequence Galβ1-3GalNAcβ1- [24]. 4Galβ1-4GlcCer. Sialic acids can be attached once, twice, or With the exception of echinoderms (marine organisms severalfold to different positions within the core structures. of typically pentaradial symmetry), gangliosides are usually Most often, they are found in α2,3-linkage to the “inner” absent from invertebrates. Arthropods, for example, form or “outer” galactosyl residue, and in α2,8-linkage to other acidic GSLs with a Manβ1,4Glcβ1,1Cer core, which contain sialic acids. Ganglioside GM1 bears one sialic acid moiety glucuronic acid instead of sialic acids. For gangliosides of connected to the 3-OH-group of the galactosyl residue in echinoderms [38–42], there is no systematic short-hand position II of the gangliotetraose moiety (see also Figure 7). nomenclature. They show structural features uncommon to The corresponding IUPAC-IUBMB short-hand name is mammalian gangliosides, such as sialic acid residues within 3 II Neu5AcGg4Cer. Structures of ganglio-series gangliosides the oligosaccharide moieties (e.g., LG-2, Figure 5), α2,11- can also be derived from the scheme of ganglioside biosyn- linked sialic acids (e.g., LLG-5, Figure 5), sialic acid methy- thesis (see below; Figure 12). In general, ganglio-series GSLs lation or sulfation, or a glycosyl inositolphosphoceramide of the 0-series bear no sialic acids on the galactose in position core, for example, [43, 44]. In cultured neurons, echinoder- II, of the a-series bear one, of the b-series bear two, and of mal gangliosides show neuritogenic and growth-inhibitory the c-series bear three sialic acid residues. However, GM1b activities. In this regard, they are more potent than other ISRN Biochemistry 3 IV III OH HO HO OH O OH Ceramide 1 HOOC HO O 3 O COOH 3 O O 2 2 OH1 II I AcHN O O HO 8 AcHN 1 O OH OH HO HO OH 1 OH HOOC O AcHN HO (CH2) CH3 OH HO O O O 12 O 2 3 1 O HN (CH2)16CH3 8 OH 4 OH HOOC 2 O AcHN OH O OH O OH Ganglioside GQ1b HO NHAcOH HO Figure 2: Structure of GQ1b, one of the most abundant gangliosides in adult human brain, which is involved in long term potentiation, synaptic plasticity, and improvement of cognitive function [23]. OH OH HO O AcHN O OH OH O OH HOOC O O O HO O OH AcHN O OH OH HO OH AcHN OH HOOC O HO OH HO O (CH2)12CH3 O O O O HN (CH2)16CH3 HO OH OH AcHN OH O OH Ganglioside GD1aGalNAc OH OH HO COOH OH O O O (CH ) CH AcHN 2 12 3 O HN OH OH HO OH (CH2) CH3 O 21 Ganglioside GM4 OH Figure 3: GD1aGalNAc and GM4.