Inhibition of Phytosterol Biosynthesis by Azasterols

Darnet, Sylvain; Martin, Laetitia B. B.; Mercier, Pierre; Bracher, Franz; Geoffroy, Philippe; Schaller, Hubert

doi:10.3390/molecules25051111

Cited by 10 publications

(7 citation statements)

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“…Compounds such as azasteroids are known to inhibit the metabolism of sterols in plants (Darnet et al, 2020), nematodes (Choi et al, 2003) and insects either by acting directly on the enzyme Δ 24 -sterol reductase or at some other step in sterol metabolism, transport or utilization (Svoboda and Weirich, 1995). In insects, they block the formation of the moulting hormone or inhibit sterol transport and utilization which is essential for insect growth and development (Entringer et al, 2021;Toprak and Musselman, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…Azasteroids are known to inhibit the pathway of conversion of phytosterols to cholesterol, thereby affecting growth, moulting and development in some insects (Svoboda and Robbins, 1971;Svoboda et al, 1972;Thompson et al, 1975;Agarwal et al, 1990). These compounds also inhibit phytosterol biosynthesis (Darnet, 2020), have antifungal properties (Burbiel and Bracher, 2013). Therefore, the role of these azasteroids on sterol metabolism pathways, targeting insect growth, could be many folds.…”

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confidence: 99%

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Effect of Dietary Azasteroids on the Growth and Development of the Gram Pod Borer Helicoverpa armigera (Hubner)

Rath

Saxena

Goel

et al. 2022

ije

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Effect of two azasteroids, 25-azacholestane and 25-azacoprostane was studied on growth and development of an economically important phytophagous pest, Helicoverpa armigera (Hubner) causing extensive damage to crops like cotton, pigeon pea, chickpea and others. 25-Azacholestane caused an increase in larval mortality (36% in control to 52% at 25 ppm), decrease in pupation (64% in control to 48% at 25 ppm) and decrease in adult emergence (60% in control to 28% at 25 ppm). Larval and pupal duration was significantly more as the azacholestane concentration increased to 25 ppm (p<0.001). Similar results were observed in case of 25-azacoprostane treatment also. Both the azasteroids were found to have inhibitory effect on the growth and development of H. armigera. Formation of larval-pupal intermediates and adults with abnormal wings was also observed. Addition of 0.1% cholesterol along with 10 ppm of 25-azacoprostane in the diet reversed the inhibitory effect of the azasteroid.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of Dietary Azasteroids on the Growth and Development of the Gram Pod Borer Helicoverpa armigera (Hubner)

Rath

Saxena

Goel

et al. 2022

ije

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“…However, the analysis of the sterol biosynthesis intermediates indicated that clomiphene interferes with cyclopropylsterol-cycloisomerase (CPI), and possibly other steps in sterol biosynthesis. Current CPI pharmacology consists of morpholines such as fenpropimorph (Taton et al ., 1987), and LDAO (Darnet et al ., 2020). Similarly to clomiphene, neither inhibitor is selective for CPI.…”

Section: Discussionmentioning

confidence: 99%

The selective estrogen receptor modulator clomiphene inhibits sterol biosynthesis inArabidopsis thaliana

Wang

Vriese

Desmet

et al. 2023

Preprint

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Sterols are produced via complex, multistep biosynthetic pathways involving similar enzymatic conversions in plants, animals and fungi, yielding a variety of sterol metabolites with slightly different chemical properties to exert diverse and specific functions. The role of plant sterols has been studied in the context of cell biological processes, signaling and overall plant development, mainly based on mutants. Due to their essential nature, genetic interference with their function causes pleiotropic developmental defects. An important alternative is to use a pharmacological approach. However, the current toolset for manipulating sterol biosynthesis in plants remains limited. Here, we probed a collection of inhibitors of mammalian cholesterol biosynthesis to identify new inhibitors of plant sterol biosynthesis. We provide evidence that imidazole-type fungicides, bifonazole, clotrimazole and econazole inhibit the obtusifoliol 14α-demethylase CYP51, that is highly conserved among eukaryotes. Surprisingly, we found that the selective estrogen receptor modulator, clomiphene, inhibits sterol biosynthesis, in part by inhibiting the plant-specific cyclopropyl-cycloisomerase CPI1. These results demonstrate that rescreening of the animal sterol biosynthesis pharmacology is an easy approach for identifying novel inhibitors of plant sterol biosynthesis. Such molecules can be used as entry points for the development of plant-specific inhibitors of sterol biosynthesis that can be used in agriculture.

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“…Phytosterol extraction was conducted as previously described by [ 79 ] using 100 mg (dry weight) of tobacco BY-2 cells. Experiences were performed in triplicate, and sterols were quantified using α-cholestane as a standard and calculated as a percentage, taking the mean of total phytosterol content in control cells as a reference.…”

Section: Methodsmentioning

confidence: 99%

Methyl-Jasmonate Functions as a Molecular Switch Promoting Cross-Talk between Pathways for the Biosynthesis of Isoprenoid Backbones Used to Modify Proteins in Plants

Chevalier,

Huchelmann,

Debié

et al. 2024

Plants

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In plants, the plastidial mevalonate (MVA)-independent pathway is required for the modification with geranylgeranyl groups of CaaL-motif proteins, which are substrates of protein geranylgeranyltransferase type-I (PGGT-I). As a consequence, fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose (DX)-5 phosphate reductoisomerase/DXR, the second enzyme in this so-called methylerythritol phosphate (MEP) pathway, also acts as an effective inhibitor of protein prenylation. This can be visualized in plant cells by confocal microscopy by expressing GFP-CaM-CVIL, a prenylation sensor protein. After treatment with fosmidomycin, the plasma membrane localization of this GFP-based sensor is altered, and a nuclear distribution of fluorescence is observed instead. In tobacco cells, a visual screen of conditions allowing membrane localization in the presence of fosmidomycin identified jasmonic acid methyl esther (MeJA) as a chemical capable of gradually overcoming inhibition. Using Arabidopsis protein prenyltransferase loss-of-function mutant lines expressing GFP-CaM-CVIL proteins, we demonstrated that in the presence of MeJA, protein farnesyltransferase (PFT) can modify the GFP-CaM-CVIL sensor, a substrate the enzyme does not recognize under standard conditions. Similar to MeJA, farnesol and MVA also alter the protein substrate specificity of PFT, whereas DX and geranylgeraniol have limited or no effect. Our data suggest that MeJA adjusts the protein substrate specificity of PFT by promoting a metabolic cross-talk directing the origin of the prenyl group used to modify the protein. MVA, or an MVA-derived metabolite, appears to be a key metabolic intermediate for this change in substrate specificity.

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Inhibition of Phytosterol Biosynthesis by Azasterols

Cited by 10 publications

References 50 publications

Effect of Dietary Azasteroids on the Growth and Development of the Gram Pod Borer Helicoverpa armigera (Hubner)

Effect of Dietary Azasteroids on the Growth and Development of the Gram Pod Borer Helicoverpa armigera (Hubner)

The selective estrogen receptor modulator clomiphene inhibits sterol biosynthesis inArabidopsis thaliana

Methyl-Jasmonate Functions as a Molecular Switch Promoting Cross-Talk between Pathways for the Biosynthesis of Isoprenoid Backbones Used to Modify Proteins in Plants

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