Abstract
At first glance, the biological function of globoside (Gb) clusters appears to be that of glycosphingolipid (GSL) receptors for bacterial toxins that mediate host-pathogen interaction. Indeed, certain bacterial toxin families have been evolutionarily arranged so that they can enter eukaryotic cells through GSL receptors. A closer look reveals this molecular arrangement allocated on a variety of eukaryotic cell membranes, with its role revolving around physiological regulation and pathological processes. What makes Gb such a ubiquitous functional arrangement? Perhaps its peculiarity is underpinned by the molecular structure itself, the nature of Gb-bound ligands, or the intracellular trafficking unleashed by those ligands. Moreover, Gb biological conspicuousness may not lie on intrinsic properties or on its enzymatic synthesis/degradation pathways. The present review traverses these biological aspects, focusing mainly on globotriaosylceramide (Gb3), a GSL molecule present in cell membranes of distinct cell types, and proposes a wrap-up discussion with a phylogenetic view and the physiological and pathological functional alternatives.
Highlights
Glycosphingolipids (GSLs) are complex lipids consisting of glycans conjugated to a ceramide core and comprise a diverse group of over 300 molecules (Table 1) (D’Angelo et al, 2013; Nakayama et al, 2013)
Phase 1 pharmacokinetics, safety, and tolerability studies of two clinically approved and used drugs for the treatment of Fabry and Gaucher disease, Eliglustat and Miglustat, are both inhibitors of glucosylceramide synthase (GCS) and have shown no adverse immunological effects (Maegawa et al, 2009; Peterschmitt et al, 2011), which is in keeping with the results described above
This review presents an overall description of the cell types expressing Gb3 and a detailed account of its physiological function in immune and renal cells
Summary
Glycosphingolipids (GSLs) are complex lipids consisting of glycans conjugated to a ceramide core and comprise a diverse group of over 300 molecules (Table 1) (D’Angelo et al, 2013; Nakayama et al, 2013). Regardless of the route taken (vesicular or non-vesicular), once GlcCer reaches the luminal side of the trans Golgi membrane, it becomes the substrate of β4Gal-T5 with the formation of LacCer, a precursor for the synthesis of globo-, ganglio-, lacto- and neolacto-series of GSLs (Budani et al, 2021; Rizzo et al, 2021). Contrary to what occurs in the synthesis of protein, RNA and DNA, the synthesis of GSLs proceeds in a template-independent manner and only depends on the order in which glycosyltransferases add specific monosaccharide residues to the growing glycan chain in the ceramide molecule through competing reactions taking place in the cisternae of the Golgi apparatus (D’Angelo et al, 2013).
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