Role of Globotriaosylceramide in Physiology and Pathology

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.

Keywords: Gb3; cancer; glycosphingolipid pathology; glycosphingolipid physiology; glycosphingolipids; hemolytic uremic syndrome.

FIGURE 1

Chemical structure of Gb3. Orange carbon chain: fatty acid. Purple carbon chain: sphingosine. Blue monosaccharide residue: glucose. Green monosaccharide residues: galactose. Black curved arrows represent a specific enzyme in the Gb3 synthesis pathway. The name of the enzyme and the link produced by the enzyme are shown above and below, respectively, in black. Red arrowheads represent a specific enzyme in the Gb3 degradation pathway. The name of the enzyme is shown below in red. Red blunt arrow represents the enzyme which is inhibited by different drugs (above in red) and indicates the changes in the fatty acid and sphingosine that can lead to the diversity of Gb3 isoforms and analogs, respectively. #: Enzyme induced by INFα. *: Enzyme induced by TNFα. GCS, glucosylceramide synthase; β4Gal-T5, β-1,4 galactosyltransferase 5; AC, acid ceramidase; α-Gal, α-galactosidase A; GALC, GalCer-β-galactosidase; GlcCer’ase, GlcCer-β-glucosidase.