PF1163A, a novel antifungal agent, inhibit ergosterol biosynthesis at C-4 sterol methyl oxidase.
PF1163A and B are a pair of antifungal agents isolated from a fermentation broth of Penicillium sp. PF1163A inhibited ergosterol synthesis in Saccharomyces cerevisiae, resulting in an accumulation of 4,4-dimethylzymosterol and a decrease of ergosterol. The ERG25 strain overexpressing the ERG25 gene was resistant to PF1163A. ERG25p is a C-4 sterol methyl oxidase known to be essential for the viability of yeast and fungi because of the known role of ERG25 gene disruption in S. cerevisiae-led lethality. ERG25p is the enzyme responsible for the first step in the removal of the two methyl groups at the C-4 position of sterol. From the results obtained here, we conclude that PF1163A is a novel natural antifungal that inhibits C-4 sterol methyl oxidase.
Nose
Hiroshi
H
Drug Discovery, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-0002, Japan. hiroshi_nose@meiji.co.jp
Fushimi
Hideki
H
Seki
Asako
A
Sasaki
Toru
T
Watabe
Hiroomi
H
Hoshiko
Shigeru
S
D000935:Antifungal Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000032:analysis / Q000096:biosynthesis*; D015870:Gene Expression; D047028:Macrocyclic Compounds; D009682:Magnetic Resonance Spectroscopy; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D013261:Sterols / Q000032:analysis
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; C405057:PF 1163A; D011994:Recombinant Proteins; D013261:Sterols; D006899:Mixed Function Oxygenases; C027532:methylsterol monooxygenase; D004875:Ergosterol