Combinatorial Ganglioside Biosynthesis (2002)

endoplasmic reticulum sialyltransferase Sphingolipids are building blocks of eukaryotic cell surfaces (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar). They anchor lipid-bound carbohydrates to the plasma membrane and contribute to the epidermal water permeability barrier of the skin. Glycolipid patterns can reach a high degree of complexity that constitutes a paradigm of combinatorial biosynthesis. During combinatorial biosynthesis, a variety of biomolecules is generated by the combination of different building blocks (2Cane D.E. Walsh C.T. Khosla C. Science. 1998; 282: 63-68Crossref PubMed Scopus (551) Google Scholar). A paradigm for this process is the humoral immune response that relies on somatic recombination of gene fragments encoding proteins of the immunoglobulin family. In contrast to the formation of antibodies, the formation of the glycolipid variety is controlled at the transcriptional and posttranscriptional level. Glycolipid patterns are generated by only a few enzymes that are expressed in a cell type- and development-dependent fashion. The limited substrate specificity of some of the glycosyltransferases involved allows combination of the carbohydrate building blocks. On the other hand, the large number of theoretically possible glycolipid structures that can be formed by combination of different carbohydrate building blocks, linkage positions, and stereochemistry is realized only to a certain extent. Only a few glycolipid series are actually found in evolutionary related species. A series is defined by sugar sequences that are part of a common carbohydrate core. Gangliosides are acidic glycosphingolipids that contain one or more sialic acid residues and are particularly prevalent on neuronal cells. They belong to the so-called ganglio-, lacto-, and neolacto-series (Fig.1). Other glycolipid series found in human tissues are the globo-, isoglobo-, and muco-series, which are all derived from lactosylceramide (Fig. 1). Sialic acids can be attached to several positions within these core structures but also to galactosylceramide, a glycolipid of the gala-series. Additional heterogeneity in the glycolipids arises from variations within the ceramide moiety, which are due to different alkyl chain lengths, the degree of hydroxylation, and desaturation. Functional consequences of heterogeneities in the lipid component have been discussed (3Lingwood C.A. Trends Glycosci. Glycotechnol. 2000; 12: 7-16Crossref Scopus (6) Google Scholar). Moreover, the sialic moiety can be heterogeneous with respect to modifications of the N-acetylneuraminic acid byO-acetylation, N-glycolylation in some species, lactonization, and others (4Traving C. Schauer R. Cell. Mol. Life Sci. 1998; 54: 1330-1349Crossref PubMed Scopus (335) Google Scholar). Glycolipid patterns vary between different cell types and change with the differentiation of the cell (5Yu R.K. Prog. Brain Res. 1994; 101: 31-44Crossref PubMed Scopus (148) Google Scholar). Differences in glycolipid composition have even been found between different neuronal cell types (6Kotani M. Kawashima I. Ozawa H. Terashima T. Tai T. Glycobiology. 1993; 3: 137-146Crossref PubMed Scopus (133) Google Scholar). For example, β1,3-N-acetylglucosaminyltransferase expression, which leads to the formation of glycolipids of the lacto- and neolacto-series, is highly regulated during embryonic development in mice and decreases after birth to undetectable levels in most cell types (7Henion T.R. Zhou D. Wolfer D.P. Jungalwala F.B. J. Biol. Chem. 2001; 276: 30261-30269Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). In adult cerebellum, it is restricted to Purkinje cells (8Chou D.K.H. Jungalwala F.B. J. Biol. Chem. 1996; 271: 28868-28874Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). The biological function of this molecular diversity is unclear, but the vital role of glycosphingolipids has been demonstrated by the fact that their complete deficiency in mice leads to early embryonic lethality (see below). Gangliosides seem to be involved in cell-to-cell interactions (9Hakomori S. Igarashi Y. J. Biochem. (Tokyo). 1995; 118: 1091-1103Crossref PubMed Scopus (365) Google Scholar) and are also reported to regulate the activities of receptor tyrosine kinases in the plasma membrane such as the receptors of epidermal growth factor (10Zhou Q. Hakomori S. Kitamura K. Igarashi Y. J. Biol. Chem. 1994; 269: 1959-1965Abstract Full Text PDF PubMed Google Scholar), nerve growth factor (11Mutoh T. Tokuda A. Miyadai T. Hamaguchi M. Fujiki N. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5087-5091Crossref PubMed Scopus (391) Google Scholar), and insulin (12Nojiri H. Stroud M. Hakomori S. J. Biol. Chem. 1991; 266: 4531-4537Abstract Full Text PDF PubMed Google Scholar) and in this way might regulate cell signaling. Gangliosides are not homogeneously distributed on the cell surface; together with glycosylphosphatidylinositol-anchored proteins, sphingomyelin, and cholesterol, they can segregate into membrane domains (rafts), which might be the physiological surroundings of many membrane proteins (13Brown D.A. London E. J. Biol. Chem. 2000; 275: 17221-17224Abstract Full Text Full Text PDF PubMed Scopus (2035) Google Scholar). Several reports indicate that physiological processes like embryogenesis and differentiation of neuronal cells and leukocytes might be influenced by gangliosides (for review, see Ref.14Riboni L. Viani P. Bassi R. Prinetti A. Tettamanti G. Prog. Lipid Res. 1997; 36: 153-195Crossref PubMed Scopus (188) Google Scholar). Just as with their functions, the mechanisms by which glycosphingolipid diversity is controlled are also beginning to be understood. We report on the principles of the ganglioside-synthesizing machinery and on recent findings from genetically engineered animals that shed light on regulation and function of these complex lipid patterns. Glycosphingolipids including gangliosides are formed biosynthetically at intracellular membranes (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar, 14Riboni L. Viani P. Bassi R. Prinetti A. Tettamanti G. Prog. Lipid Res. 1997; 36: 153-195Crossref PubMed Scopus (188) Google Scholar) from which they are transported to the plasma membrane by exocytotic membrane flow (15van Meer G. Lisman Q. J. Biol. Chem. 2002; 277: 25855-25858Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). They are degraded after endocytosis within the acidic compartments of the cell by a complex machinery of degrading enzymes, activator proteins, and negatively charged lipids (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar). Several human diseases are caused by defects in glycolipid degradation that lead to the accumulation of metabolites upstream of the defective reactions (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar). Only one human disease is caused by a biosynthetic defect (16Dawkins J.L. Hulme D.J. Brahmbhatt S.B. Auer-Grumbach M. Nicholson G.A. Nat. Genet. 2001; 27: 309-312Crossref PubMed Scopus (329) Google Scholar). A principal difference between ganglioside anabolism and catabolism is that during glycolipid formation glycolipid substrates and enzymes are membrane-bound, whereas during degradation most glycosidases are soluble enzymes that act on membrane-bound substrates. This explains in part the requirement for activator proteins for glycolipid degradation (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar), which seems not to be the case in biosynthesis. In addition, membrane-bound glycosyltransferases interact with their membrane-bound glycolipid substrates by diffusion within the two-dimensional plane of the lipid bilayer. This explains the observation that reaction rates can become independent of the reaction volume and may obey two-dimensional enzyme kinetics (17Scheel G. Acevedo E. Conzelmann E. Nehrkorn H. Sandhoff K. Eur. J. Biochem. 1982; 127: 245-253Crossref PubMed Scopus (53) Google Scholar, 18Zhou G.F. Allende M.L. Jaskiewicz E. Qian R. Darling D.S. Worth C.A. Colley K.J. Young W.W. Glycobiology. 1998; 8: 831-840Crossref PubMed Scopus (27) Google Scholar). Ganglioside biosynthesis starts with the formation of ceramide at the membranes of the endoplasmic reticulum (ER)1 (for review, see Refs.1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar and 19Merrill A.H., Jr. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar). Ceramide is the common precursor of glycosphingolipids and sphingomyelin and is transported to the Golgi apparatus by unknown mechanisms (for review, see Ref. 15van Meer G. Lisman Q. J. Biol. Chem. 2002; 277: 25855-25858Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Glycosphingolipids are synthesized by the stepwise addition of monosaccharides onto ceramide. The synthesis is coupled to bulk exocytotic vesicle flow through the Golgi apparatus to the plasma membrane (15van Meer G. Lisman Q. J. Biol. Chem. 2002; 277: 25855-25858Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Galactosylceramide (GalCer) 2Nomenclature of glycolipids is that of Svennerholm (34Svennerholm L. J. Neurochem. 1963; 10: 455-463Crossref Scopus (1297) Google Scholar) in accordance with the IUPAC recommendations (Pure Appl. Chem. (1997)69, 2475–2487).and sulfatide (GalCer-3-sulfate) are present in high concentrations in the multilamellar layers of the myelin that surrounds the axons of neuronal cells (20Coetzee T. Suzuki K. Popko B. Trends Neurosci. 1998; 21: 126-130Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The reaction of the 3′-OH group in the galactose residue of GalCer with sulfate activated as PAPS (3′-phosphoadenosine 5′-phosphosulfate) yields sulfatide (21Sundaram K.S. Lev M. J. Biol. Chem. 1992; 267: 24041-24044Abstract Full Text PDF PubMed Google Scholar). In contrast to most glycosyltransferases involved in ganglioside biosynthesis, which are type II transmembrane proteins, ceramide galactosyltransferase is a type I transmembrane protein. It has a C-terminal ER retention signal and the catalytic domain is on the luminal side of the ER (22Schulte S. Stoffel W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10265-10269Crossref PubMed Scopus (161) Google Scholar, 23Sprong H. Kruithof B. Leijendekker R. Slot J.W. van Meer G. van der Sluijs P. J. Biol. Chem. 1998; 273: 25880-25888Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). In addition to their lipid substrates, the transferases require nucleotide-activated sugars that are transported through the organellar membranes by antiporters (24Hirschberg C.B. Robbins P.W. Abeijon C. Annu. Rev. Biochem. 1998; 67: 49-69Crossref PubMed Scopus (301) Google Scholar). Although formation of galactosylceramide occurs on the luminal face of the ER membrane, the biosynthesis of sulfatide (25Tennekoon G. Zaruba M. Wolinsky J. J. Cell Biol. 1983; 97: 1107-1112Crossref PubMed Scopus (36) Google Scholar) and digalactosylceramide (26Burger K.N.J. van der Bijl P. van Meer G. J. Cell Biol. 1996; 133: 15-28Crossref PubMed Scopus (87) Google Scholar) takes place in the lumen of the Golgi apparatus. Ceramide glucosyltransferase transfers a glucose residue from UDP-glucose to ceramide (27Paul P. Kamisaka Y. Marks D.L. Pagano R.E. J. Biol. Chem. 1996; 271: 2287-2293Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 28Ichikawa S. Sakiyama H. Suzuki G. Hidari K. Hirabayashi Y. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4638-4643Crossref PubMed Scopus (208) Google Scholar). Although GlcCer and GalCer synthase catalyze similar reactions, there is no sequence homology between the cDNAs that encode these enzymes. This is obviously because of the different topology of their active sites. In contrast to most of the other sphingolipid glycosyltransferases that structurally resemble the protein glycosyltransferases, ceramide glucosyltransferase is a type III transmembrane protein. It forms non-covalent dimers or oligomers (29Marks D.L., Wu, K.J. Paul P. Kamisaka Y. Watanabe R. Pagano R.E. J. Biol. Chem. 1999; 274: 451-456Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) with their C-terminal catalytic domains in the cytosol (28Ichikawa S. Sakiyama H. Suzuki G. Hidari K. Hirabayashi Y. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4638-4643Crossref PubMed Scopus (208) Google Scholar). Because the formation of glucosylceramide occurs on the cytosolic face of the Golgi apparatus or a pre-Golgi compartment (31Coste H. Martel M.-B. Got R. Biochim. Biophys. Acta. 1986; 858: 6-12Crossref PubMed Scopus (113) Google Scholar, 32Jeckel D. Karrenbauer A. Burger K.N.J. van Meer G. Wieland F. J. Cell Biol. 1992; 117: 259-267Crossref PubMed Scopus (253) Google Scholar), ceramide, and in part dihydroceramide, has to be transported from the ER to the Golgi apparatus. Introduction of the next sugar residue that leads to the formation of lactosylceramide occurs on the luminal site of the Golgi apparatus (33Lannert H. Bünning C. Jeckel D. Wieland F.T. FEBS Lett. 1994; 342: 91-96Crossref PubMed Scopus (85) Google Scholar). This implicates a membrane translocation of glucosylceramide, which might be mediated by an as yet uncharacterized “flippase.” Translocation is energy-independent (26Burger K.N.J. van der Bijl P. van Meer G. J. Cell Biol. 1996; 133: 15-28Crossref PubMed Scopus (87) Google Scholar) and presumably incomplete, because a part of the GlcCer pool can reach the cytosolic leaflet of the plasma membrane from the cytosolic face of the Golgi apparatus (35Warnock D.E. Lutz M.S. Blackburn W.A. Young W.W. Baenziger J.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2708-2712Crossref PubMed Scopus (107) Google Scholar). The biosynthesis of higher gangliosides then occurs on the luminal face of the Golgi apparatus. Consequently, the glycan chains on the membrane-bound glycosphingolipids are orientated extracytosolically. This orientation is topologically equivalent to the situation in the plasma membrane, where the carbohydrate residues of complex glycolipids project into the extracellular space. Ganglioside biosynthesis is catalyzed by glycosyltransferases in the lumen of the Golgi apparatus (1Kolter T. Sandhoff K. Angew. Chem. Int. Ed. 1999; 38: 1532-1568Crossref PubMed Scopus (389) Google Scholar, 36Kaufman B. Basu S. Roseman S. J. Biol. Chem. 1968; 243: 5804-5807Abstract Full Text PDF PubMed Google Scholar, 37Keenan T.W. Morre D.J. Basu S. J. Biol. Chem. 1974; 249: 310-315Abstract Full Text PDF PubMed Google Scholar, 38Maccioni H.J. Daniotti J.L. Martina J.A. Biochim. Biophys. Acta. 1999; 1437: 101-118Crossref PubMed Scopus (80) Google Scholar, 39Lloyd K.O. Furukawa K. Glycoconj. J. 1998; 15: 627-636Crossref PubMed Scopus (114) Google Scholar, 52Roseman S. Chem. Phys. Lipids. 1970; 5: 270-297Crossref PubMed Scopus (799) Google Scholar). With the exception of ganglioside GM4 (3′-sialyl-GalCer), a major component of myelin (40Ledeen R.W., Yu, R.K. Eng L.F. J. Neurochem. 1973; 21: 829-839Crossref PubMed Scopus (469) Google Scholar), gangliosides are structurally and biosynthetically derived from lactosylceramide. Lactosylceramide, the common precursor of the glycosphingolipid series that are found in vertebrates, is formed by the action of galactosyltransferase I, which transfers a galactose residue from UDP-galactose to glucosylceramide. The enzyme has been purified from rat brain and cloned (41Nomura T. Takizawa M. Aoki J. Arai H. Inoue K. Wakisaka E. Yoshizuka N. Imokawa G. Dohmae N. Takio K. Hattori M. Matsuo N. J. Biol. Chem. 1998; 273: 13570-13577Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Further sugar residues, including sialic acids, are transferred in a stepwise manner to the growing glycan chains. Lactosylceramide and its sialylated derivatives, the hematosides GM3, GD3, and GT3, serve as precursors for complex gangliosides of the 0-, a-, b-, and c-series (Fig.2). These different series are characterized by the presence of no (0-series), one (a-series), two (b-series), or three sialic acid residues (c-series) linked to the 3-position of the inner galactose moiety. In adult human tissues, gangliosides from the 0- and c-series are found only in The transferases that catalyze the in ganglioside biosynthesis high specificity their glycolipid the formation of GM3, and The of these glycolipids in the seem to the of glycolipids that are derived only from gangliosides that are only derived from ganglioside GM3, and gangliosides that are only derived from ganglioside the stepwise of these precursors is by only a few glycosyltransferases of limited like on an They the sugar residue to that only in the number of sialic acids to the inner I and II are more for their glycolipid substrates and or galactosyltransferase II and This and to there is also no in It that different transferases catalyze the formation of the different gangliosides in The of the transferases demonstrated by enzyme kinetics G. D. G. D. Sandhoff K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, H. van G. Sandhoff K. Eur. J. 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The animals similar like the animals with defective galactosylceramide different of mice have been generated that are not to the major gangliosides found in the brain of the In accordance with the of ganglioside biosynthesis, mice with a deficiency of on are not to the major gangliosides and and mice with sialyltransferase II on gangliosides GD3, and only of brain mice K. A. Furukawa K. S. M. M. S. M. N. K. M. M. H. Furukawa K. S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar) defects in the Further and defects in the J. Y. H. J.W. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). with these findings the mice defects in function S. J. 2000; PubMed Scopus Google Scholar). defects found also in The mice and and defects in the K. A. Furukawa K. J. S. S. M. M. M. M. H. S. Furukawa K. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). their immune the response of cells to J. Furukawa K. S. M. R. H. K. S. H. T. Furukawa K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The molecular for these are of the gene encoding sialyltransferase which is for the formation of ganglioside and the gangliosides to animals with a and defects H. Allende M.L. R. M. K. C. T. N. U. Sandhoff K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The in the of and other gangliosides during neuronal development and have to the that these gangliosides might be for neuronal it has been that embryonic cells with a sialyltransferase II gene neuronal differentiation even in the of gangliosides H. K. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). This is also in with the of the ganglioside expression, sialyltransferase II mice with mice a gene encoding The mice on expressed only ganglioside as their major ganglioside H. Allende M.L. R. M. K. C. T. N. U. Sandhoff K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast to sialyltransferase II the to of by and a This a vital role of the physiological ganglioside for neuronal function and A recent generated is a sialyltransferase on The mice are not to ganglioside of the gangliosides found in the of and at of the A. N. R. K. and R. L. have been from the of ganglioside biosynthesis, they gangliosides of the and in that to the ganglioside of The mice glucose with an insulin receptor The indicate that ganglioside is an of and recent that contribute to type II S. K. H. Kitamura F. S. C. A. M. U. S. Igarashi Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The most is the with and sialyltransferase I on N. R. K. and R. L. mice are not to glycolipid of the Lactosylceramide concentrations are to in the of the In addition, lactosylceramide sulfate with and acid composition similar to gangliosides has been in these The found gangliosides are of other sialic glycolipids that are present also in brain The recent development of genetically engineered mice with defects in of ganglioside synthesis of the function of ganglioside diversity found on cells.