Regulation of sterol biosynthesis in sunflower by 24(R,S),25-epiminolanosterol, a novel C-24 methyl transferase inhibitor

Nes, W. David; Janssen, Giselle G.; Norton, R. A.; Kalinowska, Małgorzata; Crumley, Farrist G.; Tal, Beni; Bergenstråhle, Annika; Jonsson, Lisbeth

doi:10.1016/0006-291x(91)92021-b

Cited by 26 publications

(23 citation statements)

References 10 publications

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“…Biochemical and in vivo radiolabeling studies have suggested that SMT is a rate-limiting enzyme and may regulate the biosynthesis of 24-alkyl sterols (Guo et al, 1995;Fang and Baisted, 1975;Parker and Nes, 1992;Nes et al, 1991aNes et al, , 1991b. Recently, it has been shown that transgenic tobacco plants overexpressing the hydroxymethylglutaryl-CoA reductase accumulate a large amount of cycloartenol, providing further evidence for the role of SMT in the regulation of phytosterol biosynthesis (Chappell et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…1). The C-24 methylation step has been implicated as a rate-limiting step in sterol transformations (Guo et al, 1995;Fang and Baisted, 1975;Parker and Nes, 1992;Nes et al, 1991aNes et al, , 1991bChappell et al, 1995). In animals, instead of a C-24 methylation in the side chain of cycloartenol, a reduction of the ⌬ 24 -double bond in the side chain of lanosterol takes place, leading to cholesterol biosynthesis.…”

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confidence: 99%

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Identification and Characterization of an S-Adenosyl-L-methionine:Δ24-Sterol-C-methyltransferase cDNA from Soybean

Shi

Gonzales

Bhattacharyya

1996

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Identification and Characterization of an S-Adenosyl-L-methionine:Δ24-Sterol-C-methyltransferase cDNA from Soybean

Shi

Gonzales

Bhattacharyya

1996

Journal of Biological Chemistry

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“…Sterol analogs with positive charges at specific loca tions of its side chains have been found to be very effective inhibitors of 24(25)-SMT and growth inhibitors of yeasts, fungi, plants and protozoa in vitro [15,16,[20][21][22][23] but to the best of our knowledge there have been no reports on their successful therapeutic appli cation in vivo. In the present study we found that two of these inhibitors, a cholestanol ana log with a 6-membcred aza ring as a side chain (22,AZA, fig. 1A) [18,19] and 24-('/?,5J,25-epiminolanosterol (EIL, fig.…”

Section: Inhibitors On T Cruzimentioning

confidence: 99%

“…1A) [18,19] and 24-('/?,5J,25-epiminolanosterol (EIL, fig. IB) [16,21,22] are potent growth inhibitors against T. cruzi, in vitro and in vivo and that these effects are potentiated by C-14a-demethylase inhibitors such as ketoconazole and SDZ 89,485. …”

Section: Inhibitors On T Cruzimentioning

confidence: 99%

Antiproliferative Effects of △<sup>24(25)</sup> Sterol Methyl Transferase Inhibitors on <i>Trypanosoma (Schizotrypanum) cruzi</i>: In vitro and in vivo Studies

et al. 1996

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We have studied the antiproliferative effects of two sterol analogs previously reported as potent inhibitors of Δ²⁴⁽²⁵⁾ sterol methyl transferase (E.C. 2.1.1.43) of yeasts and fungi on epimastigotes and amastigotes on Trypanosoma (Schizotrypanum) cruzi, the causative agents of Chagas disease, as well as its chemotherapeutic effecs in a murine model of the disease. On the epimastigote form proliferating in liver infusion tryptose medium at 28 C 22,26-azasterol (AZA), a cholestanol analog with a 6-membered aza ring as a side chain produced a dose-dependent reduction of the growth rate up to 3 µM, but at 10 µM complete growth arest and cell lysis took place after 120-144 h. For 24(R, S), 25-epiminolanosterol (EIL), complete growth arrest and lysis took place with 6 µM. In both cases the antiproliferative effects were potentiated by the simultaneous incubation of the epimastigotes with inhibitors of sterol C-14α-demethylase such as ketoconazole or SDZ 89,485, as indicated by concave isobolograms and fractional inhibitory concentrations ranging from 0.11 to 0.46. Analysis of the sterol composition in control and treated cells by thin-layer and capillary gas-liquid chromatography coupled to mass spectrometry showed that growth inhibition correlated with the complete disappearance of the native endogenous sterols of the parasite (ergosterol and 24-ethyl analogs) and the accumulation of 24-desalkyl sterols. Against the clinically relevant amastigote form proliferating inside cultured Vera cells at 37°C, AZA eradicated the parasite of 100 nM, while the corresponding concentration for EIL was 300 nM. Synergic effects of both inhibitors when combined with ketoconazole against this form of the parasite was demonstrated using a three-dimensional analytic method which allowed the identification of optimal drug concentrations. Finally, it was found that daily oral administration of AZA at 50 mg/kg/day for a total of 43 doses to mice infected with a lethal inoculum of T. cruzi allowed survival of all treated animals 25 days after infection, while all control (untreated) animals were dead at this point of time. Increased survival correlated with a 90% reduction in parasitemia in the treated animals. The antiparasitic effects of the azasterol were potentiated in combined treatments with ketoconazole. This is the first report of a successful application of a sterol methyl transferase inhibitor as a chemotherapeutic agent in a protozoal infection.

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“…In contrast to animals, higher plants contain mixtures of 24-alkyl-⌬ 5 -sterols, of which campesterol is the principal 24-methyl sterol, and sitosterol and stigmasterol are the predominant 24-ethyl sterols (Schaller et al, 1998). It has been proposed that the C-24 methylation of cycloartenol is a major site of regulation in the sterol biosynthetic pathway (Nes et al, 1991;Chappell et al, 1995;Nes, 2000). Important evidence supporting this view is that transgenic tobacco (Nicotiana tabacum) leaf-overexpressing 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) accumulates high levels of cycloartenol, but only relatively moderate levels of 24-alkyl-⌬ 5 -sterols (Chappell et al, 1995;Schaller et al, 1995).…”

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confidence: 99%

Sterol C-24 Methyltransferase Type 1 Controls the Flux of Carbon into Sterol Biosynthesis in Tobacco Seed

et al. 2002

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The first committed step in the conversion of cycloartenol into ⌬ 5 C24-alkyl sterols in plants is catalyzed by an S-adenosylmethionine-dependent sterol-C24-methyltransferase type 1 (SMT1). We report the consequences of overexpressing SMT1 in tobacco (Nicotiana tabacum), under control of either the constitutive carnation etched ring virus promoter or the seed-specific Brassica napus acyl-carrier protein promoter, on sterol biosynthesis in seed tissue. Overexpression of SMT1 with either promoter increased the amount of total sterols in seed tissue by up to 44%. The sterol composition was also perturbed with levels of sitosterol increased by up to 50% and levels of isofucosterol and campesterol increased by up to 80%, whereas levels of cycloartenol and cholesterol were decreased by up to 53% and 34%, respectively. Concomitant with the enhanced SMT1 activity was an increase in endogenous 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, from which one can speculate that reduced levels of cycloartenol feed back to up-regulate 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and thereby control the carbon flux into sterol biosynthesis. This potential regulatory role of SMT1 in seed sterol biosynthesis is discussed.

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Regulation of sterol biosynthesis in sunflower by 24(R,S),25-epiminolanosterol, a novel C-24 methyl transferase inhibitor

Cited by 26 publications

References 10 publications

Identification and Characterization of an S-Adenosyl-L-methionine:Δ24-Sterol-C-methyltransferase cDNA from Soybean

Identification and Characterization of an S-Adenosyl-L-methionine:Δ24-Sterol-C-methyltransferase cDNA from Soybean

Antiproliferative Effects of △<sup>24(25)</sup> Sterol Methyl Transferase Inhibitors on <i>Trypanosoma (Schizotrypanum) cruzi</i>: In vitro and in vivo Studies

Sterol C-24 Methyltransferase Type 1 Controls the Flux of Carbon into Sterol Biosynthesis in Tobacco Seed

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