Mode of action of famoxadone

✍ Scribed by Jordan, Douglas B; Livingston, Robert S; Bisaha, John J; Duncan, Keith E; Pember, Stephen O; Picollelli, Michael A; Schwartz, Rand S; Sternberg, Jeffrey A; Tang, Xiao-Song

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 440 KB
• Volume: 55
• Category: Article
• ISSN: 1526-498X
• DOI: 10.1002/(sici)1096-9063(199902)55:2<105::aid-ps879>3.0.co;2-d

✦ Synopsis

Famoxadone is a preventative and curative fungicide recently developed for plant disease control. The molecule and its oxazolidinone analogs (OADs) are potent inhibitors of mitochondrial electron transport, speciücally inhibiting the function of the enzyme ubiquinol :cytochrome c oxidoreductase (cytochrome Visible absorbance spectral studies on the puriüed enzyme suggested that bc 1 ). famoxadone bound close to the low potential heme of cytochrome b. This binding mode was conürmed in competitive binding experiments by studying the displacement of a radiolabelled OAD from submitochondria. EPR studies on the binding of famoxadone to submitochondria and puriüed suggested its binding mode was more like that of myxothiazol than that of stigmatellin (ligands bc 1 known to bind near the low potential heme). Zoospores of Phytophthora infestans, when given low concentrations of famoxadone and other OADs, were observed to cease oxygen consumption and motility within seconds and later the cells disintegrated, releasing the cellular contents. Famoxadone was a potent inhibitor of the growth of Saccharomyces cerevisiae when grown on non-fermentable carbon sources and it was an approximately 50-fold less potent inhibitor of growth when the yeast was grown on a fermentable carbon source, glucose. Such physiological observations are consistent with the loss of mitochondrial function imposed by famoxadone and OADs. Single amino acid changes in the apocytochrome b of baker's yeast cytochrome b located near the low potential heme altered the inhibition constants for the inhibitors famoxadone, myxothiazol, azoxystrobin and kresoxim-methyl diþ erentially, thus strongly suggesting diþ erent binding interactions of the protein with the inhibitors.