Current relevance of fungal and trypanosomatid glycolipids and sphingolipids: studies defining structures conspicuously absent in mammals

Abstract

Recently, glycosphingolipids have been attracting attention due to their role on biological systems as second messengers or modulators of signal transduction, affecting several events, which range from apoptosis to regulation of the cell cycle. In pathogenic fungi, glycolipids are expressed in two classes: neutral monohexosylceramides (glucosyl-or galactosylceramide) and acidic glycosylinositol phosphorylceramides (the latter class carries longer glycan chains). It is worth to mention that monohexosylceramides exhibit significant structural differences in their lipid moieties compared to their mammalian counterparts, whereas the glycosylinositol phosphorylceramides exhibit remarkable structural differences in their carbohydrate moieties in comparison to mammal glycosphingolipids counterpart. We observed that glycosylinositol phosphorylceramides are capable of promoting immune response in infected humans. In addition, inhibiting fungal glycosphingolipid biosynthetic pathways leads to an inhibition of colony formation, spore germination, cell cycle, dimorphism and hyphal growth. Other pathogens, such as trypanosomatids, also present unique glycolipids, which may have an important role for the parasite development and/or disease establishment. Regarding host-pathogen interaction, cell membrane rafts, which are enriched in sphingolipids and sterols, participate in parasite/fungal infection. In this review, it is discussed the different biological roles of (glyco)(sphingo)lipids of pathogenic/opportunistic fungi and trypanosomatids.

Structural diversity and biological significance of glycosphingolipids in pathogenic and opportunistic fungi

“…Similar results were observed when P. brasiliensis, H. capsulatum, S. schenckii , and C. neoformans were cultivated in the presence of P4 (Takahashi et al, 2009). It is worth mentioning that antimicrobial peptides, such as the plant defensin RsAFP2, also display antifungal activity against Candida isolates by interaction with fungal GlcCer (Tavares et al, 2008; Thevissen et al, 2012; Silva et al, 2014).…”

“…Another feature that is particular to fungal GlcCer/GalCer is the (E)-Δ 3 -unsaturation and the presence of a hydroxyl group linked to C2 of the fatty acid moiety, having either N-2′-hydroxyoctadecanoate (h18:0) or the unsaturated form N-2′-hydroxy-(E)-3′-octadecenoate (h18:1) [(E)-13-unsaturated fatty acid] (Takahashi et al, 2009). GlcCer from mycelium forms of Paracoccidioides brasiliensis and Histoplasma capsulatum present a higher percentage of unsaturated fatty acids, indicating that the temperature change which induces the transition of mycelium to yeast forms possibly activates a fatty acid desaturase (Toledo et al, 1999, 2001).…”

“…The glycan structures of fungal GIPCs are built-up on three different “cores”: (i) GlcNα1-2Ins; (ii)Manα1-6Ins; and (iii) Manα1-2Ins. The glycosylation of IPCs seems to occur upon a ceramide mainly composed by t18:0 4-hydroxysphinganine (phytosphingosine) and h24:0 fatty acid (Takahashi et al, 2009). It is worth mentioning that the lipid moiety of these GIPCs when compared to glucosyl- and galactosylceramide displayed different sphingosines, with 4,8-diene-9-methyl-sphingo base as precursor for GlcCer/GalCer synthesis, and phytosphingosine for IPC synthesis, suggesting a dichotomy in the biosynthetic pathway of fungal neutral and acidic GSLs (Leipelt et al, 2001).…”

“…In dihydroceramides, a desaturase inserts a double bound at C4 converting it in ceramide (Rhome et al, 2007). In fungi Glc or Gal residues are transferred to ceramide in the assembly of GlcCer or GalCer whereas the more complex glycan moieties of GIPCs are built up on phytoceramide (Takahashi et al, 2009). After glycosylation, GSLs are transported to the outer leaflet of the cell membrane forming membrane microdomains, also as described by Longo et al (2013), GlcCer may also be found in lipid vesicles in the cell wall, probably being part of the exocytosis transport system.…”

Biosynthesis of the Fungal Cell Wall Polysaccharide Galactomannan Requires Intraluminal GDP-mannose

“…In fungi, GDP-Man transport is indispensable for modification of protein N-and O-glycans (28 -30), glycolipid biosynthesis (31), and GPI anchor substitution (32,33). It has been reported to be essential in Saccharomyces (21), Candida (23), and Aspergillus niger (26).…”