title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA. slevery@cisunix.unh.edu
authors.forename: Steven B
authors.initials: SB
authors.lastname: Levery
authors.forename: Michelle
authors.initials: M
authors.lastname: Momany
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lindsey
authors.forename: Marcos S
authors.initials: MS
authors.lastname: Toledo
authors.forename: James A
authors.initials: JA
authors.lastname: Shayman
authors.forename: Matthew
authors.initials: M
authors.lastname: Fuller
authors.forename: Kelly
authors.initials: K
authors.lastname: Brooks
authors.forename: Ron Lou
authors.initials: RL
authors.lastname: Doong
authors.forename: Anita H
authors.initials: AH
authors.lastname: Straus
authors.forename: Helio K
authors.initials: HK
authors.lastname: Takahashi
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D001233:Aspergillus nidulans / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002554:Cerebrosides / Q000032:analysis / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005699:Galactosylceramides / Q000032:analysis / Q000096:biosynthesis; D005963:Glucosylceramides / Q000032:analysis / Q000096:biosynthesis*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025301:Hyphae / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000494:pharmacology; D013172:Spores, Fungal / Q000187:drug effects
chemical_list: C465358:1-phenyl-2-palmitoyl-3-pyrrolidinopropanol; C465359:3',4'-ethylenedioxy-1-phenyl-2-palmitoyl-3-pyrrolidinepropanol; D000935:Antifungal Agents; D002247:Carbon Isotopes; D002554:Cerebrosides; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D005699:Galactosylceramides; D005963:Glucosylceramides; D011759:Pyrrolidines; D005964:Glucosyltransferases