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.
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.
Levery
Steven B
SB
Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA. slevery@cisunix.unh.edu
Momany
Michelle
M
Lindsey
Rebecca
R
Toledo
Marcos S
MS
Shayman
James A
JA
Fuller
Matthew
M
Brooks
Kelly
K
Doong
Ron Lou
RL
Straus
Anita H
AH
Takahashi
Helio K
HK
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
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