Combinatorial Ganglioside Biosynthesis

Abstract

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 glycosylphosphatid