Abstract
Glycosphingolipids (GSLs) are ubiquitous membrane components and have key roles in biological systems, acting as second messengers or modulators of signal transduction by affecting several events, ranging from cell adhesion, cell growth, cell motility, regulation of apoptosis and cell cycle. Over the last 20 years our laboratory and other research groups determined the glycan and ceramide structures of more than 20 GSLs from several pathogenic/opportunistic fungi, using a combination of gas chromatography, mass spectrometry, nuclear magnetic resonance as well as other immunochemical and biochemical techniques. Fungal GSLs can be divided in two major classes: neutral GSLs, galactosyl- and glucosylceramide (GlcCer), and acidic GSLs, the glycosylinositol-phosphorylceramides (GIPCs). Glycosyl structures in fungal GIPCs exhibited significant structural diversity and distinct composition when compared to mammalian GSLs, e.g., the expression of inositol-mannose and inositol-glucosamine cores and the terminal residue of β-D-galactofuranose which are absent in mammalian cells. Studies performed by our group demonstrated that GIPC (Galfβ 6[Manα3]Manα2InsPCer) elicited in patients with paracoccidioidomycosis an immune response with production of antibodies directed to the terminal residue of β-D-galactofuranose. Further studies also showed that inhibition of GlcCer biosynthetic pathways affects fungal colony formation, spore germination and hyphal growth, indicating that enzymes involved in GlcCer biosynthesis may represent promising targets for the therapy of fungal infections. Recently, it was shown that GlcCer and GIPCs are preferentially localized in membrane microdomains and monoclonal antibodies directed to these GSLs interfere in several fungal biological processes such as growth and morphological transition. This review focuses on glycan structures carried on sphingolipids of pathogenic/opportunistic fungi, and aspects of their biological significance are discussed.
Highlights
Glycosphingolipids (GSLs) are ubiquitous membrane components present mostly in the outer leaflet of the plasma membrane with their carbohydrate head groups exposed to the extracellular space, and mainly organized in microdomains by association with sterols and specific proteins.The glycosphingolipid biosynthesis starts by the action of serine palmitoyltransferase which condensates palmitoyl-CoA with serine forming 3-keto-sphinganine, the keto group is reduced to hydroxyl group forming the dihydrosphingosine, at this point, as shown in Figure 1, the dihydrosphingosine may be hydroxylated on the C4 to form the phytosphingosine (4-hydroxysphinganine)
Our laboratory and other research groups have characterized a number of neutral GSLs, glucosyl- and galactosylceramide (GlcCer and GalCer), as well as acidic GSLs—the glycosylinositolphosphorylceramides (GIPCs) from pathogenic/opportunistic fungi, using a combination of high performance thin layer chromatography (HPTLC), gas chromatography/mass spectrometry (GC/MS), single quadrupole mass spectrometry, 1H/13C nuclear magnetic resonance—Correlation Spectroscopy (COSY), Total Correlation Spectroscopy (TOCSY), Nuclear Overhauser Effect Spectroscopy (NOESY) as well as other immunochemical and biochemical techniques
We have demonstrated that mAb MEST-3, an IgG2a directed to Manpα3Manpα2IPC, interfered on colony formation and morphological transition from yeast to mycelium of P. brasiliensis, H. capsulatum and S. schenckii
Summary
Reviewed by: Charlene Kahler, University of Western Australia, Australia Leonardo Nimrichter, Federal University of Rio de Janeiro, Brazil Hua Xie, Meharry Medical College, USA. Glycosyl structures in fungal GIPCs exhibited significant structural diversity and distinct composition when compared to mammalian GSLs, e.g., the expression of inositol-mannose and inositol-glucosamine cores and the terminal residue of β-D-galactofuranose which are absent in mammalian cells. Studies performed by our group demonstrated that GIPC (Galf β6[Manα3]Manα2InsPCer) elicited in patients with paracoccidioidomycosis an immune response with production of antibodies directed to the terminal residue of β-D-galactofuranose. It was shown that GlcCer and GIPCs are preferentially localized in membrane microdomains and monoclonal antibodies directed to these GSLs interfere in several fungal biological processes such as growth and morphological transition. This review focuses on glycan structures carried on sphingolipids of pathogenic/opportunistic fungi, and aspects of their biological significance are discussed
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