Analysis of glycosylinositol phosphorylceramides expressed by the opportunistic mycopathogen Aspergillus fumigatus

Toledo, Marcos S.; Levery, Steven B.; Bennion, Beau; Guimarães, Luciana Lopes; Castle, Sherry A.; Lindsey, Rebecca L.; Momany, Michelle; Park, Chaeho; Straus, Anita H.; Takahashi, Hélio K.

doi:10.1194/jlr.m700149-jlr200

Cited by 41 publications

(38 citation statements)

References 62 publications

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“…Deletion of gmtA is thus expected to abrogate transport of GDP-Man in the Golgi apparatus and interfere with biosynthesis of glycoconjugates. GIPCs, whose structures have been comprehensively described (42,43), have thus been analyzed by MALDI-TOF mass spectrometry. The core structure Man␣1-3Man␣1-2IPC (Hex 2 -IPC) can be modified by mannose and/or galactofuranose, yielding GIPCs with three or four hexoses (Hex 3 -and Hex 4 -IPCs).…”

Section: A Fumigatus Gmta Is An Active Gdp-man Transporter-mentioning

confidence: 99%

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

Engel

Schmalhorst

Routier

2012

Journal of Biological Chemistry

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Background: Understanding the mechanisms of cell wall biogenesis is important for development of antifungal strategies. Results: Biosynthesis of the fungal polysaccharide galactomannan requires import of GDP-mannose into the Golgi apparatus. Conclusion: It differs from the biosynthesis of other fungal cell wall polysaccharides.Significance: This provides a new paradigm for cell wall polysaccharide biosynthesis.

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Section: A Fumigatus Gmta Is An Active Gdp-man Transporter-mentioning

confidence: 99%

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

Engel

Schmalhorst

Routier

2012

Journal of Biological Chemistry

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“…Nominal, monoisotopic m/z values are used in the labeling and description of ϩ ESI-MS results. Interpretation of spectra derived from [MϩNa] ϩ and [MϩLi] ϩ adducts of phytoceramides was essentially as described previously for the ceramide moieties of fungal glycosylceramides and glycosylinositol phosphorylceramides (38,74).…”

Section: Cell Survival Measurementsmentioning

confidence: 99%

Stress-Induced Cell Death Is Mediated by Ceramide Synthesis in Neurospora crassa

et al. 2008

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The combined stresses of moderate heat shock (45°C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells are particularly sensitive to exogenous ceramide, which is lethal at low concentrations. When we extracted endogenous sphingolipids, we found that unique ceramides were induced (i) by the inhibitory glucose analog 2-deoxyglucose and (ii) by combined heat shock and 2-deoxyglucose. We determined that the former is a 2-deoxyglucose-modified ceramide. By structural analysis, we identified the latter, induced by dual stress, as C 18 (OH)-phytoceramide. We also identified C 24 (OH)-phytoceramide as a constitutive ceramide that continues to be produced during the combined stresses. The unusual C 18 (OH)-phytoceramide is not made by germinating asexual spores subjected to the same heat and carbon stress. Since these spores, unlike growing cells, do not die from the stresses, this suggests a possible connection between synthesis of the dual-stress-induced ceramide and cell death. This connection is supported by the finding that a (dihydro)ceramide synthase inhibitor, australifungin, renders cells resistant to death from these stresses. The OS-2 mitogen-activated protein kinase, homologous to mammalian p38, may be involved in the cell death signaling pathway. Strains lacking OS-2 survived the combined stresses better than the wild type, and phosphorylated OS-2 increased in wild-type cells in response to heat shock and combined heat and carbon stress.

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“…Besides being an abundant component of the extracellular matrix, secreted galactomannans are used for serological diagnostic of invasive aspergillosis (1). The monosaccharide Galf has also been found in the N-and O-glycans of some glycoproteins as well as the glycosphingolipids of A. fumigatus (23,29,41,47) and thus represents an important constituent of the cell wall of this fungus. Galf is otherwise infrequent in natural compounds but prevalent in pathogens.…”

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confidence: 99%

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

et al. 2008

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The filamentous fungus Aspergillus fumigatus is responsible for a lethal disease called invasive aspergillosis that affects immunocompromised patients. This disease, like other human fungal diseases, is generally treated by compounds targeting the primary fungal cell membrane sterol. Recently, glucan synthesis inhibitors were added to the limited antifungal arsenal and encouraged the search for novel targets in cell wall biosynthesis. Although galactomannan is a major component of the A. fumigatus cell wall and extracellular matrix, the biosynthesis and role of galactomannan are currently unknown. By a targeted gene deletion approach, we demonstrate that UDP-galactopyranose mutase, a key enzyme of galactofuranose metabolism, controls the biosynthesis of galactomannan and galactofuranose containing glycoconjugates. The glfA deletion mutant generated in this study is devoid of galactofuranose and displays attenuated virulence in a low-dose mouse model of invasive aspergillosis that likely reflects the impaired growth of the mutant at mammalian body temperature. Furthermore, the absence of galactofuranose results in a thinner cell wall that correlates with an increased susceptibility to several antifungal agents. The UDP-galactopyranose mutase thus appears to be an appealing adjunct therapeutic target in combination with other drugs against A. fumigatus. Its absence from mammalian cells indeed offers a considerable advantage to achieve therapeutic selectivity.

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Analysis of glycosylinositol phosphorylceramides expressed by the opportunistic mycopathogen Aspergillus fumigatus

Cited by 41 publications

References 62 publications

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

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

Stress-Induced Cell Death Is Mediated by Ceramide Synthesis in Neurospora crassa

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

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