Chemical structure-activity relationships of the inhibition of sterol biosynthesis by N-substituted morpholines in higher plants

Rahier, Alain; Schmitt, Paulette; Huss, Brigitte; Benveniste, Pierre; Pommer, E. H.

doi:10.1016/0048-3575(86)90038-6

Cited by 60 publications

(23 citation statements)

References 21 publications

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“…This compound is known to mainly inhibit the cycloeucalenol-obtusifoliol isomerase (Rahier et al, 1986). In a previous report (Hartmann et al, 2002), we have shown that treatment of leek seedlings with FEN induced an accumulation of 9b,19-cyclopropylsterols in place of the usual D 5 -sterols.…”

Section: Discussionmentioning

confidence: 98%

“…We have determined the intracellular distribution of lipid microdomains in leek (Allium porrum) seedlings by preparing DRMs from ER-, GA-, and PM-enriched fractions and probed the involvement of sterols in microdomain formation by treatment with fenpropimorph (FEN), a sterol biosynthesis inhibitor that inhibits the cycloeucalenol-obtusifoliol isomerase (Rahier et al, 1986) and induces an accumulation of 9b,19-cyclopropylsterols in place of the usual D 5 -sterols (Hartmann et al, 2002). We have shown that most of the DRMs normally originate from the PM but that they are more abundant in the GA instead of the PM in FEN-treated plants.…”

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confidence: 99%

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Insights into the Role of Specific Lipids in the Formation and Delivery of Lipid Microdomains to the Plasma Membrane of Plant Cells

et al. 2006

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The existence of sphingolipid-and sterol-enriched microdomains, known as lipid rafts, in the plasma membrane (PM) of eukaryotic cells is well documented. To obtain more insight into the lipid molecular species required for the formation of microdomains in plants, we have isolated detergent (Triton X-100)-resistant membranes (DRMs) from the PM of Arabidopsis (Arabidopsis thaliana) and leek (Allium porrum) seedlings as well as from Arabidopsis cell cultures. Here, we show that all DRM preparations are enriched in sterols, sterylglucosides, and glucosylceramides (GluCer) and depleted in glycerophospholipids. The GluCer of DRMs from leek seedlings contain hydroxypalmitic acid. We investigated the role of sterols in DRM formation along the secretory pathway in leek seedlings. We present evidence for the presence of DRMs in both the PM and the Golgi apparatus but not in the endoplasmic reticulum. In leek seedlings treated with fenpropimorph, a sterol biosynthesis inhibitor, the usual D 5 -sterols are replaced by 9b,19-cyclopropylsterols. In these plants, sterols and hydroxypalmitic acid-containing GluCer do not reach the PM, and most DRMs are recovered from the Golgi apparatus, indicating that D 5 -sterols and GluCer play a crucial role in lipid microdomain formation and delivery to the PM. In addition, DRM formation in Arabidopsis cells is shown to depend on the unsaturation degree of fatty acyl chains as evidenced by the dramatic decrease in the amount of DRMs prepared from the Arabidopsis mutants, fad2 and Fad31, affected in their fatty acid desaturases.Despite the ongoing debate on the size, lifespan, and dynamics of lipid microdomains (Munro, 2003;Pike, 2004;Nichols, 2005;Hancock, 2006), the existence of sterol-and sphingolipid-enriched membrane microdomains in the plasma membrane (PM) of eukaryotic cells is now well recognized (Simons and Ikonen, 1997;Brown and London, 2000;Simons and Toomre, 2000;Bagnat and Simons, 2002;Simons and Vaz, 2004;Hancock, 2006). Evidence for microdomains comes in part from examination of membrane constituents that are resistant to solubilization by nonionic detergents at low temperature, giving rise to the concept of lipid rafts (Simons and Ikonen, 1997;Brown and London, 1998;Rö per et al., 2000;Hancock, 2006). Such steroland sphingolipid-enriched microdomains can be isolated as detergent-resistant membranes (DRMs). In the following, the terms of DRMs and microdomains will be assigned to respectively indicate the isolated entities and the corresponding membrane entities. Lipid properties of microdomains are similar to liquid-ordered domains, which are characterized by tightly packed hydrocarbon tails but with a high degree of lateral mobility (Brown and London, 2000;Simons and Vaz, 2004). Cholesterol is thought to contribute to the tight packing of lipids in liquid-ordered domains by filling interstitial spaces between lipid molecules (Brown, 1998)

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Insights into the Role of Specific Lipids in the Formation and Delivery of Lipid Microdomains to the Plasma Membrane of Plant Cells

et al. 2006

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“…The absence of obtusifoliol (9) and the accumulation of 9f3, 19-cyclopropyl sterols demonstrate that COI, the enzyme which catalyzes the opening of the cyclopropane ring of cycloeucalenol (10) to give obtusifoliol (9), is the major target of such morpholines in plants. At physiological pH, these morpholines are protonated, and the resulting morpholinium ions behave like analogs of the carbocationic high energy intermediate involved in the reaction (24). They are very potent inhibitors ofCOI.…”

Section: Discussionmentioning

confidence: 99%

“…They are very potent inhibitors ofCOI. For instance, an I50 value of 0.4 tLM was measured in a cell-free system of maize embryos in the presence of fenpropimorph (24). Fenpropimorph was also reported to be an inhibitor of the A8-A7 sterol isomerase (30).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas animal and fungal cells generally contain one major sterol, respectively, cholesterol (1)1 and ergosterol (17), ' Chemical nomenclature: cholesterol (1), cholest-5-en-3,B-ol; 24-methyl cholesterol (2), (24r)-24-methylcholest-5-en-3(3-ol; stigmasterol (3), (24S)24-ethylcholesta-5,22E-dien-33-ol; sitosterol (4), (24R)-24-ethylcholest-5-en-3f3-ol; isofucosterol (5), stigmasta -5,24 (28)Z-dien-3f-ol; 24-methyl pollinastanol (6), (24r)-24,14a-dimethyl-9fl, 19-cyclo-5a-cholestan-3#-ol; 24-methylene pollinastanol (7), 14a-methyl-9f,19-cyclo-5a-ergost-24(28)-en-33-ol; 24-ethyl pollinastanol (8), 14a-methyl-9j3, 19-cyclo-5a-stigmastan-3f-ol; obtusifoliol (9), 4a, 14a-dimethyl-5a-ergosta-8,24(28)-dien-3(-ol; cycloeucalenol (10), 4a, 14a-dimethyl-9(, 19-cyclo-5a-ergost-24(28)-en-3(-ol; 24-dihydrocycloeucalenol (11), (24R)-24,4a, 14a-trimethyl-9,B, 19-cyclo-5a-cholestan-3,B-ol; 31-norcyclobranol (12), 4a,14a-dimethyl-9,3,19-cyclo-5a-ergost-24(25)-en-3fl-ol; cyclofuntumienol (13), 4a, 14a-dimethyl-93,19-cyclo-5a-stigmast-24(28)Z-en-3,3-ol; cycloartenol (14), 4,4,14a-trimethyl-9,B, 19-cyclo-5a-cholest-24-en-3,-ol; 24methylene cycloartanol (15), 4,4,14a-trimethyl-93, 19-cyclo-5a-ergost-24(28)-en-33-ol; f-amyrin (16), olean-12-en-3,B-ol; ergosterol (17), (24R)-24-methylcholesta-5,7,22E-trien-3,B-ol; fenpropimorph, (R,S)-4-[3-(4-tert-butylphenyl)-2-methyl-propyl]-2,6-dimethylmorpholine.…”

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Cyclopropyl Sterol and Phospholipid Composition of Membrane Fractions from Maize Roots Treated with Fenpropimorph

Grandmougin¹,

Bouvier-Navé²,

Ullmann³

et al. 1989

Plant Physiol.

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Maize (Zea mays L.) caryopses were grown in the presence of fenpropimorph, a systemic fungicide, for 7 days in the dark. Membrane fractions enriched, respectively, in endoplasmic reticulum, plasma membrane, and mitochondria were isolated from control and treated maize roots and analyzed for their free sterol, phospholipid, and fatty acid composition. In treated plants, the intracellular distribution of free sterols was dramatically modified both qualitatively and quantitatively. The normally occurring A5-sterols disappeared almost completely and were replaced by 9,B,19-cyclopropyl sterols, mainly cycloeucalenol and 24-methyl pollinastanol. These new compounds were found to accumulate in all the membrane fractions in such a way that the endoplasmic reticulum-rich fraction became the richest one in free sterols instead of the plasma membrane. In contrast, the fenpropimorph treatment of maize roots was shown not to affect either the relative proportions or the amounts of the individual phospholipids, but an increase in the unsaturation index of phospholipidfatty acyl chains of the endoplasmic reticulum-rich fraction was observed. The present data suggest that, in higher plant membranes, cyclopropyl sterols could play a structural role similar to that of the bulk of A5-sterols.Whereas animal and fungal cells generally contain one major sterol, respectively, cholesterol (1)1 and ergosterol (17), ' Chemical nomenclature: cholesterol (1), cholest-5-en-3,B-ol; 24-methyl cholesterol (2), (24r)-24-methylcholest-5-en-3(3-ol; stigmas-(28)Z-dien-3f-ol; 24-methyl pollinastanol (6), (24r)-24,14a-dimethyl-9fl, 19-cyclo-5a-cholestan-3#-ol; 24-methylene pollinastanol (7), 14a-methyl-9f,19-cyclo-5a-ergost-24(28)-en-33-ol; 24-ethyl pollinastanol (8), 14a-methyl-9j3, 19-cyclo-5a-stigmastan-3f-ol; obtusifoliol (9), 4a, 14a-dimethyl-5a-ergosta-8,24(28)-dien-3(-ol; cycloeucalenol (10), 4a, 14a-dimethyl-9(, 19-cyclo-5a-ergost-24(28)-en-3(-ol; 24-dihydrocycloeucalenol (11), (24R)-24,4a, 14a-trimethyl-9,B, 19-cyclo-5a-cholestan-3,B-ol; 31-norcyclobranol (12), 4a,14a-dimethyl-9,3,19-cyclo-5a-ergost-24(25)-en-3fl-ol; cyclofuntumienol (13), 4a, 14a-dimethyl-93,19-cyclo-5a-stigmast-24(28)Z-en-3,3-ol; cycloartenol (14), 4,4,14a-trimethyl-9,B, 19-cyclo-5a-cholest-24-en-3,-ol; 24-methylene cycloartanol (15), 4,4,14a-trimethyl-93, 19-cyclo-5a-ergost-24(28)-en-33-ol; f-amyrin (16), olean-12-en-3,B-ol; ergosterol (17), (24R)-24-methylcholesta-5,7,22E-trien-3,B-ol; fenpropimorph, (R,S)-4-[3-(4-tert-butylphenyl)-2-methyl-propyl]-2,6-dimethylmorpholine.in most higher plants, sterols are present as mixtures in which 24-methyl cholesterol (2), stigmasterol (3), and sitosterol (4) often predominate (20). These A5-sterols mostly accumulate in the plasma membrane (pM)2 (13), where they are believed to regulate the membrane fluidity and, consequently, the activity of membrane-bound enzymes. In addition to this structural role, a few sterol molecules might be involved in metabolic functions. To obtain a better insight into sterol functions in plant...

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Rationally Designed Guanidine and Amidine Fungicides

Liebeschuetz¹,

Katz²,

Duriatti³

et al. 1997

Pestic. Sci.

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: A previous investigation established that compounds containing a guanidinium or amidinium grouping are e †ective inhibitors of sterol *8È*7 isomerase and/or *14 reductase activity in plant pathogenic fungi. A binding model for known fungicidal inhibitors of this enzyme has now been used to rationally design further guanidinium or amidinium inhibitors. Three novel classes of chemistry were investigated. The results of biochemical testing against ergosterol biosynthesis in Ustilago maydis (DC) Corda and of in-vivo testing for fungicidal activity against Erysiphe graminis DC f. sp. hordei Marchal (powdery mildew of barley), do much to support the binding model, and compounds with signiÐcant fungicidal activity have been found.

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Chemical structure-activity relationships of the inhibition of sterol biosynthesis by N-substituted morpholines in higher plants

Cited by 60 publications

References 21 publications

Insights into the Role of Specific Lipids in the Formation and Delivery of Lipid Microdomains to the Plasma Membrane of Plant Cells

Insights into the Role of Specific Lipids in the Formation and Delivery of Lipid Microdomains to the Plasma Membrane of Plant Cells

Cyclopropyl Sterol and Phospholipid Composition of Membrane Fractions from Maize Roots Treated with Fenpropimorph

Rationally Designed Guanidine and Amidine Fungicides

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