Overlapping and Distinct Roles of Aspergillus fumigatus UDP-glucose 4-Epimerases in Galactose Metabolism and the Synthesis of Galactose-containing Cell Wall Polysaccharides

Abstract

Background:Aspergillus fumigatus produces two galactose-containing exopolysaccharides, galactomannan and galactosaminogalactan. Results: Galactosaminogalactan synthesis requires the UDP-glucose 4-epimerases, Uge5 and Uge3, whereas galactomannan synthesis requires Uge5 alone. Conclusion: Epimerases in A. fumigatus play both distinct and overlapping roles in exopolysaccharide synthesis. Significance: Uncovering the biosynthetic pathways of galactosaminogalactan will be crucial in developing therapeutics targeting this exopolysaccharide.

Biofilm Exopolysaccharides of Pathogenic Fungi: Lessons from Bacteria

“…Synthesis of GAG begins with the production of UDP-galactopyranose (Gal) and UDP-GalNAc from UDP-glucose and UDP-GlcNAc, respectively, by the bifunctional cytosolic epimerase Uge3 (8,10). The activity and substrate specificity of this enzyme has been confirmed in vitro (10) and Uge3-deficient mutants produce no detectable GAG (8).…”

“…Galactomannan, which consists of a mannan core decorated with ␤-1,5-linked galactofuranose, is dispensable for biofilm formation, and galactofuranose-deficient mutants exhibit increased biofilm formation as a consequence of increased production of GAG (8,10,16). ␣-Glucans are abundant within the biofilm matrix; however, the role of this polysaccharide in biofilm formation has not been studied (13,(17)(18)(19).…”

Host Cell Invasion by Medically Important Fungi

“…Mutant strains expressing GalNAc-poor GAG are less adherent to host cells, whereas those expressing galactose-poor GAG retain normal adherence to host cells and macromolecules. Furthermore, as a result of the poor adherence of GAG-deficient mutants to host cells, these mutants are also defective in invading and damaging these cells Lee et al 2013); the epithelial or endothelial cell receptors to which GAG binds are not known. In addition to mediating adherence, GAG also suppresses inflammation by several mechanisms.…”

“…GAG on the surface of hyphae conceals b-glucan from recognition by the pattern-recognition receptor dectin-1 on leukocytes much in the same way that hydrophobins conceal b-glucan in resting conidia . Further, GAG can directly induce leukocyte apoptosis via an uncharacterized mechanism, and administration of GAG to mice worsens outcomes during experimental infection with A. fumigatus (Fontaine et al 2011; Lee et al 2013). Strains deficient in GAG are hypovirulent (Gravelat et al 2010, although the relative contribution of GAG-mediated adherence and immunosuppression to virulence is undefined and the subject of ongoing study.…”

“…Recently, the secreted and cell wall associated exopolysaccharide galactosaminogalactan (GAG) has been found to play a major role in mediating adherence of hyphae to basement membrane macromolecules as well as endothelial and epithelial cells (Gravelat et al 2010Lee et al 2013). GAG is a heteroglycan composed of variable amounts of galactose and N-acetyl-galactosamine (GalNAc), which is found in the outer layer of the cell wall as well as within the interstitial matrix of fungal biofilms in vitro and in vivo (Loussert et al 2010;Fontaine et al 2011).…”