Glycosphingolipid biosynthesis

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Glycosphingolipid de novo biosynthesis starts with the formation of ceramide to which the individual saccharide units are linked one after the other by stepwise additions (Fig. 39). The ceramide assigned to higher glycosphingolipids is glucosylated by a glucosyl-transferase [Paul et al., 1996], whereas that assigned to sphingomyelin flip-flops to the lumenal side of the stack, where its conversion to sphingomyelin occurs [Diringer et al., 1972]. The ceramide moiety acting as a precursor of Gal-ceramide and sulphatide remains in the endoplasmic reticulum, turns to the lumenal side of the membrane, is galactosylated by the action of a ceramide galactosyl-transferase [Schulte et al., 1993], and then transferred to the lumenal Golgi stack. Here, it is submitted to sulphation by a sulphate transferase involving PAPS (3'- phosphoadenosine, 5'-phosphosulphate) [Sunderam et al., 1992]. Probably, Gal-ceramide is sialosylated to GM4 ganglioside at the same site by the action of a sialyl-transferase (SAT I?) [Kolter et al., 2002]. Glc-ceramide turns, by a yet uncharacterized flippase, to the lumenal side of the cis-Golgi stack, where further glycosylations take place (see the scheme of ganglioside biosynthesis given in Figure 39). The first glycosylation, specifically catalysed by lactosyl-ceramide synthase is galactosylation of Glc-ceramide to lactosyl-ceramide (Lac-ceramide) [Nomurova et al., 1998]. Lac-ceramide is sialosylated to GM3 ganglioside, GM3 to GD3, and GD3 to GT3. The three involved sialyl-transferase (SAT I, SAT II and SAT III) specifically recognize the acceptor substrate [Huwiler et al., 2000; Kolter et al., 2002]. GM3, GD3 and GT3 are the starting points for the "a-series", "b-series" and "c-series" gangliosides, respectively. Along each series, non-specific N-acetylgalactosaminyl-transferase, galactosyl-transferase and sialyl-transferase (SAT IV) introduce in sequence a residue of N-acetylgalactosamine, galactose and sialic acid, respectively, giving rise to more complex gangliosides. Further sialosylations can be accomplished by sialosyl-transferase V (SAT V). From lact-ceramide, a further series of glycosphingolipids ("O-series") can originate from the sequential action of Nacetylgalactosaminyl- transferase, galactosyl-transferase and sialyl-transferase IV and V, producing GA2 (asialo-GM2), GA1 (asialo-GM1), and gangliosides GM1b, GD1c and GD1 . It should be noted that SAT I, IV and V catalyse the formation of 2 3 sialosyl linkage to galactose, SAT II and III of 2 8 sialosyl linkage to sialic acid, and a yet uncharacterized sialyl-transferase (SAT X, possibly SAT V) of 2 6 sialosyl linkage to Nacetylgalactosamine. There is some evidence for a gradient distribution of the glycosyltransferases in the Golgi system, with earlier glycosylations prevailing in the cis/medial Golgi and later glycosylations in the trans-Golgi/trans -Golgi network [Kolter et al., 2002]. This would implicate a flow (possibly vesicular) of intermediates from one Golgi stack to the following one (as in the case of glycoproteins). However, there are cases of glycosyltransferases that constitute multi-component complexes [Giraudo et al., 2001] where the product of the first enzyme is immediately processed by the following enzyme till it reaches the final product. This evidence would support the hypothesis [Roseman 1970] that a multiglycosyl- transferase complex is responsible for the synthesis of each individual ganglioside.

fig to be added 31 may 2011 noragon

The final products of glycosphingolipid biosynthesis are assumed to leave the Golgi stacks, or the trans-Golgi network, as budding vesicles and to reach and fuse with the plasma membrane. The fact that the saccharide chains of glycosphingolipids are built up in the lumenal side of Golgi membranes and exposed on the external leaflet of the plasma membrane favours the hypothesis of a vesicular transport of glycosphingolipids from the Golgi apparatus to the plasma membrane.


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