Disruption of the glucosylceramide biosynthetic pathway in Aspergillus nidulans and Aspergillus fumigatus by inhibitors of UDP-Glc:ceramide glucosyltransferase strongly affects spore germination, cell cycle, and hyphal growth

• Published in: FEBS letters Vol. 525; no. 1; pp. 59 - 64
• Main Authors: Levery, Steven B, Momany, Michelle, Lindsey, Rebecca, Toledo, Marcos S, Shayman, James A, Fuller, Matthew, Brooks, Kelly, Doong, Ron Lou, Straus, Anita H, Takahashi, Helio K
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 14.08.2002
• Subjects: Antifungal Agents - pharmacology; Aspergillus fumigatus - chemistry; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - metabolism; Aspergillus nidulans - chemistry; Aspergillus nidulans - drug effects; Aspergillus nidulans - metabolism; Carbon Isotopes; Cell Cycle - drug effects; Cell Division - drug effects; Cerebrosides - analysis; Cerebrosides - biosynthesis; CMH, ceramide monohexoside (≡cerebroside); Enzyme Inhibitors - pharmacology; ESI, electrospray ionization; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; Fungus; Galactosylceramides - analysis; Galactosylceramides - biosynthesis; GalCer, β-galactopyranosylceramide (≡galactocerebroside); GCS, glucosylceramide synthase; GIPC, glycosylinositol phosphorylceramide; GlcCer, β-glucopyranosylceramide (≡glucocerebroside); Glucosylceramides - analysis; Glucosylceramides - biosynthesis; Glucosyltransferases - antagonists & inhibitors; Glucosyltransferases - metabolism; Glycolipid; Glycosyltransferase; GSL, glycosphingolipid; HPTLC, high performance thin layer chromatography; Hyphae - drug effects; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; PDMP; PDMP, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol; Pyrrolidines - pharmacology; Sphingolipid; Spores, Fungal - drug effects; Synthase; Glycosyltransferase; CMH, ceramide monohexoside (≡cerebroside); Sphingolipid; Synthase; ESI, electrospray ionization; GCS, glucosylceramide synthase; GalCer, β-galactopyranosylceramide (≡galactocerebroside); Glycolipid; Fungus; PDMP; PDMP, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol; HPTLC, high performance thin layer chromatography; GIPC, glycosylinositol phosphorylceramide; GSL, glycosphingolipid; GlcCer, β-glucopyranosylceramide (≡glucocerebroside)
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(02)03067-3

The opportunistic mycopathogen Aspergillus fumigatus expresses both glucosylceramide and galactosylceramide (GlcCer and GalCer), but their functional significance in Aspergillus species is unknown. We here identified and characterized a GlcCer from Aspergillus nidulans, a non-pathogenic model fungus. Involvement of GlcCer in fungal development was tested on both species using a family of compounds known to inhibit GlcCer synthase in mammals. Two analogs, D- threo-1-phenyl-2-palmitoyl-3-pyrrolidinopropanol (P4) and D- threo-3′,4′-ethylenedioxy-P4, strongly inhibited germination and hyphal growth. Neutral lipids from A. fumigatus cultured in the presence of these inhibitors displayed a significantly reduced GlcCer/GalCer ratio. These results suggest that synthesis of GlcCer is essential for normal development of A. fumigatus and A. nidulans.