Glycosphingolipid degradation

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Ganglioside catabolism consists of the sequential removal of individual sugar residues, starting from the non-reducing terminal unit, by(exo)glycohydrolases with the formation of ceramide, which is eventually split into long chain base and fatty acid by ceramidase (Fig. 40) [Huwiler et al., 2000; Kolter et al., 2002; Gatt 1966]. The flux of degradation occurs through the endocytosis-endosome-lysosome pathway, and all the enzymatic steps of the degradative process require an acidic pH inside the organelle. This condition is warranted by the action of a proton pump that brings H+ inside the organelle [Huwiler et al., 2000]. Since intralysosomal glycohydrolases are soluble and the inner face of the lysosomal membrane is rich in glycoconjugates resistant to these enzymes, it has been postulated that after endocytosis, a vesiculation process occurs at the level of the endosomal membrane leading to the formation of invaginating vesicles carrying gangliosides on their external layer. After endosome fusion with lysosomes, the gangliosides are exposed in these vesicles toward the lysosomal matrix, where the soluble glycohydrolases are located and are thus available for degradation [Huwiler et al., 2000]. The sequence of sugar removal from gangliosides is as follows (see the scheme given in Fig. 3). First, multi-sialogangliosides are transformed by sialidase to the corresponding monosialogangliosides GM1, and GM2, or Lac-ceramide (from GM3). From GM1, galactose is then removed to produce GM2, and from GM2, the N-acetylgalactosamine residue split off to form GM3, by the action of a (non-specific) β-galactosidase and β-N-acetylhexosaminidase, respectively. In some cells and animals, sialic acid is removed from GM1 and GM2 by a specific sialidase producing the corresponding asialoderivatives GA1 and GA2, that by the action of β-galactosidase and β-N-acetylhexosaminidase, are converted to Lac-ceramide by a double or single reaction. Lac-ceramide is then degraded to ceramide by the sequential action of a β-galactosidase and β-glucosidase. In vivo, intralysosomal degradation of most, if not all, glycosphingolipids requires, besides exoglycohydrolases, effector molecules, of protein nature, named "sphingolipid activator proteins (SAPs, or saposines)" [Huwiler et al., 2000]. Some saposines originate from a common precursor protein (prosaposin) by a selective proteolytic cleavage [Huwiler et al., 2000].

fig to be added 31 may 2011

An alternative pathway for ganglioside (and, in general, glycosphingolipid) degradation consists of the splitting of the β-glucosidic linkage between glucose and ceramide, with the formation of ceramide and the oligosaccharide (Fig. 41). The enzymes catalysing this reaction, named "endoglycoceramidases" or "ceramide glycanases" [Ito et al., 1986; Zhou et al., 1989] appear to require, or to be markedly activated, by the presence of specific activator protein(s), seemingly soluble, whose action would be essential under in vivo conditions [Ito et al., 1991]. Endoglycoceramidases have been found to occur in some bacteria [Ito et al., 1986] and leeches [Zhou et al., 1989]. Although described to occur in lactating mammary glands of rodents [Basu et al., 1997], the presence of this enzyme in vertebrate, and, particularly, mammalian tissues, is yet to be definitely assessed.

fig to be added 31 may 2011

Sphingolipid activator proteins (SAPs) are small, enzymatically inactive glycoproteins that are essential cofactors in the degradation of glycosphingolipids with short oligosaccharide headgroups (Schuette 2001). SAP A–D are highly homologous proteins and are produced by proteolytic processing from a single precursor protein, which is called prosaposin.

table to be added 31 may 2011


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