Inositol phosphoryl transferases from human pathogenic fungi

Abstract

The IPC1 gene from Saccharomyces cerevisiae, which encodes inositolphosphorylceramide (IPC) synthase, was first identified as a novel and essential gene encoding resistance to the natural product antifungal aureobasidin A (AUR1). The formation of IPC in fungi is essential for viability, suggesting inhibitors of IPC1p function would make ideal antifungal drug candidates. Homologs of the AUR1/IPC1 gene were identified from a number of human pathogenic fungi, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis and Cryptococcus neoformans. Comparison of these genes with other homologous genes from Candida albicans, Aspergillus fumigatus, Aspergillus nidulans, Saccharomyces cerevisiae and Schizosaccharomyces pombe reveals a conserved structural motif for inositolphosphoryl transferases which is similar to a motif recently described for lipid phosphatases, but with unique characteristics.

Newly Discovered Neutral Glycosphingolipids in Aureobasidin A-resistant Zygomycetes

“…As shown in Fig. 1A, AbA strongly inhibits the growth of filamentous fungi such as A. oryzae, P. oxalicum, and Acremonium sp., previously reported for the yeast Saccharomyces cerevisiae (W303-1A) and other fungi (7)(8)(9)(10)13). However, growth inhibition by AbA was not observed for any Zygomycetes species such as M. hiemalis, R. microsporus, R. pusillus, and A. corymbifera (Fig.…”

“…Aureobasidin A is well known and widely used as an antifungal agent for Eumycetes including yeasts and fungi. It exhibits strong fungicidal activity against many pathogenic fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (7,8). Recent studies (6) have shown that this antifungal agent inhibits IPC synthase in fungal cells.…”

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

“…CPI production requires the product of the AUR1 gene, 45 a protein containing the C2 and C3 active site motifs characteristic for members of the lipid phosphate phosphatase (LPP) superfamily. 57 A database search for novel sequences encoding integral membrane proteins containing the C2 and C3 domains common to Aur1p and LPPs identified three families of candidate SM synthase ( y CSS) genes with homologues in multiple animal species 58 (Fig. 3).…”

“…57,58 Both groups of enzymes contain a six times membrane-spanning core domain with the termini facing the cytosol and the putative C2 and C3 active site residues facing the exoplasmic leaflet (Fig. 4).…”

Pleofungins, Novel Inositol Phosphorylceramide Synthase Inhibitors, from Phoma sp. SANK 13899

“…Pleofungin A more strongly inhibited IPC synthase of A. fumigatus than that of S. cerevisiae in our experimental conditions, however, aureobasidin A showed an opposing tendency in the effects on those enzymes to pleofungin A. Pleofungin A also showed stronger growth inhibition against A. fumigatus and Cryptococcus neoformans than against Candida species and S. cerevisiae. It was previously indicated that the homology between Aspergillus and yeast IPC synthase genes is very low [20,21], regardless of the high homology among the enzymes of Aspergillus species, such as A. fumigatus and A. nidulans. Our data suggested that pleofungin A may recognize the structural differences between the Aspergillus-and yeast-type enzymes, and preferably interact with Aspergillus-type enzymes.…”