In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and determination of the molecular basis of the antifungal property

Marcireau, Christophe; Guilloton, Michel; Karst, Francis

doi:10.1128/aac.34.6.989

Cited by 111 publications

(86 citation statements)

References 21 publications

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“…5A). The evidence that the Erg2 protein is the target of fenpropimorph is conflicting; in vitro binding (22) and sterol analysis following compound exposure (20,21) support Erg2 as a target, whereas the fact that in vivo overexpression of Erg2 does not confer resistance to fenpropimorph [whereas overexpression of Erg24 does (ref. 5 and data not shown)] argues against it.…”

Section: Resultsmentioning

confidence: 99%

“…Fenpropimorph is a member of the class of agricultural antifungals known as the morpholines. Fenpropimorph is thought to target both C-8 sterol isomerase (encoded by the ERG2 gene) and C-14 sterol reductase (encoded by the ERG24 gene) based on sterol analysis and in vivo data (5,20,21). In the optimal concentration window of 2.3 M fenpropimorph, the HIP assay detects ERG24 but not ERG2 sensitivity (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Giaever

Flaherty

Kumm

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

461

415

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We demonstrate the efficacy of a genome-wide protocol in yeast that allows the identification of those gene products that functionally interact with small molecules and result in the inhibition of cellular proliferation. Here we present results from screening 10 diverse compounds in 80 genome-wide experiments against the complete collection of heterozygous yeast deletion strains. These compounds include anticancer and antifungal agents, statins, alverine citrate, and dyclonine. In several cases, we identified previously known interactions; furthermore, in each case, our analysis revealed novel cellular interactions, even when the relationship between a compound and its cellular target had been well established. In addition, we identified a chemical core structure shared among three therapeutically distinct compounds that inhibit the ERG24 heterozygous deletion strain, demonstrating that cells may respond similarly to compounds of related structure. The ability to identify on-and-off target effects in vivo is fundamental to understanding the cellular response to small-molecule perturbants.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Giaever

Flaherty

Kumm

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

461

415

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“…The non-saponifiable lipid fraction was analysed by gas chromatography with a Varian 3300 chromatograph using a 30m DB5 capillary column (0.32 mm internal diameter), a ross injector, carrier gas helium (3 ml/min), column oven temperature programmed at 200Ϫ270°C at 10°/min, at 270Ϫ280°C at 0.5°/min and at 280Ϫ300°C at 10°/min. All samples were tested without Me 3Si derivatization, prepared for chromatography by adding 1 µg ignosterol before extraction as an internal standard and quantified by the area method comparatively to Ignosterol [14]. Usual methods with Me 3Si derivatization were used as controls but the chromatogram patterns were identical so, subsequent, samples were tested without Me 3 Si derivatization.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, cells were centrifuged at 800 g after detachment by scraping in the case of adherent cells, washed twice with 150 mM NaCl, 1.5 mM KH 2 PO 4 , 8.3 mM Na 2 HPO 4 , 12 H 2 O, pH 7.4 (NaCl/P i ) and frozen at Ϫ20°C. Sterols were extracted as described [14]. Briefly, saponification was performed at 80°C in the presence of KOH (10%) and methanol.…”

Section: Methodsmentioning

confidence: 99%

Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step

Bouteiller

Jamme

David

et al. 1998

European Journal of Biochemistry

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SR31747A is a new sigma ligand exhibiting immunosuppressive properties and antiproliferative activity on lymphocyte cells. Only two subtypes of sigma receptor, namely the sigma 1 receptor and emopamilbinding protein, have been characterised molecularly. Only the σ 1 receptor has been shown to bind (Z)Ncyclohexyl-N-ethyl-3-(3-chloro4-cyclohexylphenyl)propen-2-ylamine hydrochloride (SR31747A) with high affinity. It was demonstrated that the SR31747A effect on the inhibition of T-cell proliferation was consistent with a sigma 1 receptor-mediated event. In this report, binding experiments and sterol isomerase assays, using recombinant yeast strains, indicate that the recently cloned emopamil-binding protein is a new SR31747A-binding protein whose activity is inhibited by SR31747A. Sterol analyses reveal the accumulation of a ∆8-cholesterol isomer at the expense of cholesterol in SR31747A-treated cells, suggesting that cholesterol biosynthesis is inhibited by SR31747A at the ∆8-∆7 sterol isomerase step in animal cells. This observation is consistent with a sterol isomerase role of the emopamil-binding protein in the cholesterol biosynthetic pathway in animal cells. In contrast, there is no evidence for such a role of the sigma 1 receptor, in spite of the structural similarity shared by this protein and yeast sterol isomerase. We have found that SR31747A also exerts anti-proliferative effects at nanomolar concentrations on various established cell lines. The antiproliferative activity of SR31747A is reversed by cholesterol. Sterol-isomerase overproduction enhances resistance of CHO cells. This last observation strongly suggests that sterol isomerase is implicated in the antiproliferative effect of the drug in established cell lines.

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“…Inhibition of the sterol C-14 reductase and sterol D 8 -D 7 isomerase leads to deficiency of ergosterol, but accumulation of fecosterol or D 8 -sterols, which are toxic to fungal cells (Lorenz & Parks, 1991;Marcireau et al, 1990;Steel et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

A sterol C-14 reductase encoded by FgERG24B is responsible for the intrinsic resistance of Fusarium graminearum to amine fungicides

Liu

Yun

et al. 2011

Microbiology

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Fusarium graminearum, the causal agent of wheat head blight, shows intrinsic resistance to amine fungicides. It is commonly accepted that the amines target sterol C-14 reductase and sterol D 8 -D 7 isomerase of ergosterol biosynthesis, encoded by the genes ERG24 and ERG2, respectively. Analysis of the genome sequence of F. graminearum revealed that the fungus contains two paralogous FgERG24 genes (FgERG24A and FgERG24B), which are homologous to the ERG24 of Saccharomyces cerevisiae. In this study, we disrupted FgERG24A and FgERG24B in F. graminearum. Compared to the wild-type strain HN9-1, FgERG24A and FgERG24B deletion mutants did not show recognizable phenotypic changes in mycelial growth on potato dextrose agar or in virulence on wheat heads. HPLC analysis showed that the amount of ergosterol in FgERG24A or FgERG24B deletion mutants was not significantly different from that in the wild-type strain. These results indicate that neither of the two genes is essential for growth, pathogenicity or ergosterol biosynthesis in F. graminearum. FgERG24B deletion mutants exhibited significantly increased sensitivity to amine fungicides, including tridemorph, fenpropidin and spiroxamine, but not to non-amine fungicides. In contrast, FgERG24A deletion mutants did not show changed sensitivity to any amine tested. The resistance of the FgERG24B deletion mutant to amines was restored by genetic complementation of the mutant with wild-type FgERG24B. These results indicate that FgERG24B controls the intrinsic resistance of F. graminearum to amines. The finding of this study provides new insights into amine resistance in filamentous fungi.

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In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and determination of the molecular basis of the antifungal property

Cited by 111 publications

References 21 publications

Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step

A sterol C-14 reductase encoded by FgERG24B is responsible for the intrinsic resistance of Fusarium graminearum to amine fungicides

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