Inhibition of Phytosterol Biosynthesis by Azasterols

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2020 Mar 6

PMID 32131509

Citations 3

Authors

Sylvain Darnet

Laetitia B B Martin

Pierre Mercier

Franz Bracher

Philippe Geoffroy

Hubert Schaller

Affiliations

Soon will be listed here.

Abstract

Inhibitors of enzymes in essential cellular pathways are potent probes to decipher intricate physiological functions of biomolecules. The analysis of sterol profiles upon treatment with a series of azasterols reveals a specific in vivo inhibition of SMT2, a plant sterol-C-methyltransferase acting as a branch point between the campesterol and sitosterol biosynthetic segments in the pathway. Side chain azasteroids that modify sitosterol homeostasis help to refine its particular function in plant development.

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References

Lovato M, Hart E, Segura M, Giner J, Matsuda S . Functional cloning of an Arabidopsis thaliana cDNA encoding cycloeucalenol cycloisomerase. J Biol Chem. 2000; 275(18):13394-7. DOI: 10.1074/jbc.275.18.13394. View

Diener A, Li H, Zhou W, Whoriskey W, Nes W, Fink G . Sterol methyltransferase 1 controls the level of cholesterol in plants. Plant Cell. 2000; 12(6):853-70. PMC: 149089. DOI: 10.1105/tpc.12.6.853. View

Bouvier-Nave P, Husselstein T, Benveniste P . Two families of sterol methyltransferases are involved in the first and the second methylation steps of plant sterol biosynthesis. Eur J Biochem. 1998; 256(1):88-96. DOI: 10.1046/j.1432-1327.1998.2560088.x. View

Darnet S, Schaller H . Unleashed sterol production in thale cress. Nat Plants. 2019; 5(11):1112-1113. DOI: 10.1038/s41477-019-0541-6. View

Nes W, Zhou W, Ganapathy K, Liu J, Vatsyayan R, Chamala S . Sterol 24-C-methyltransferase: an enzymatic target for the disruption of ergosterol biosynthesis and homeostasis in Cryptococcus neoformans. Arch Biochem Biophys. 2008; 481(2):210-8. DOI: 10.1016/j.abb.2008.11.003. View

Waterman M, Lepesheva G . Sterol 14 alpha-demethylase, an abundant and essential mixed-function oxidase. Biochem Biophys Res Commun. 2005; 338(1):418-22. DOI: 10.1016/j.bbrc.2005.08.118. View

Renard D, Perruchon J, Giera M, Muller J, Bracher F . Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis. Bioorg Med Chem. 2009; 17(23):8123-37. DOI: 10.1016/j.bmc.2009.09.037. View

Leaver D, Patkar P, Singha U, Miller M, Haubrich B, Chaudhuri M . Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei. Chem Biol. 2015; 22(10):1374-83. PMC: 4624405. DOI: 10.1016/j.chembiol.2015.08.017. View

Corey E, Matsuda S, Bartel B . Isolation of an Arabidopsis thaliana gene encoding cycloartenol synthase by functional expression in a yeast mutant lacking lanosterol synthase by the use of a chromatographic screen. Proc Natl Acad Sci U S A. 1993; 90(24):11628-32. PMC: 48037. DOI: 10.1073/pnas.90.24.11628. View

10.

Rendeli N, Misso N, Goad L . Biosynthesis of 24-methylcholest-5-en-3β-ol and 24-ethylcholest-5-en-3β-ol inZea mays. Lipids. 2016; 21(1):63-8. DOI: 10.1007/BF02534304. View

11.

Muller C, Junker J, Bracher F, Giera M . A gas chromatography-mass spectrometry-based whole-cell screening assay for target identification in distal cholesterol biosynthesis. Nat Protoc. 2019; 14(8):2546-2570. DOI: 10.1038/s41596-019-0193-z. View

12.

Taton M, Benveniste P, Rahier A . Microsomal delta 8,14-sterol delta 14-reductase in higher plants. Characterization and inhibition by analogues of a presumptive carbocationic intermediate of the reduction reaction. Eur J Biochem. 1989; 185(3):605-14. DOI: 10.1111/j.1432-1033.1989.tb15156.x. View

13.

Rahier A, Narula A, Benveniste P, Schmitt P . 25-Azacycloartanol, a potent inhibitor of S-adenosyl-L-methionine-sterol-C-24 and C-28 methyltransferases in higher plant cells. Biochem Biophys Res Commun. 1980; 92(1):20-5. DOI: 10.1016/0006-291x(80)91513-2. View

14.

Rahier A, Bouvier P, Cattel L, Narula A, Benveniste P . Inhibition of 2,3-oxidosqualene: beta-amyrin-cyclase, S-adenosyl-L-methionine: cycloartenol C-24-methyltransferase and cycloeucalenol: obtusifoliol isomerase by rationally designed molecules containing a tertiary amine function. Biochem Soc Trans. 1983; 11(5):537-43. DOI: 10.1042/bst0110537. View

15.

Sonawane P, Pollier J, Panda S, Szymanski J, Massalha H, Yona M . Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism. Nat Plants. 2016; 3:16205. DOI: 10.1038/nplants.2016.205. View

16.

Ohyama K, Suzuki M, Kikuchi J, Saito K, Muranaka T . Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis. Proc Natl Acad Sci U S A. 2009; 106(3):725-30. PMC: 2621255. DOI: 10.1073/pnas.0807675106. View

17.

Zhou W, Ramos E, Zhu X, Fisher P, Kidane M, Vanderloop B . Steroidal antibiotics are antimetabolites of Acanthamoeba steroidogenesis with phylogenetic implications. J Lipid Res. 2019; 60(5):981-994. PMC: 6495176. DOI: 10.1194/jlr.M091587. View

18.

Kuchta T, Leka C, Kubinec R, Russell N . Inhibition of ergosterol biosynthesis is not accompanied by a change in fatty acid composition in Saccharomyces cerevisiae treated with the antifungal agent 6-amino-2-n-pentylthiobenzothiazole. FEMS Microbiol Lett. 1997; 150(1):43-7. DOI: 10.1111/j.1574-6968.1997.tb10347.x. View

19.

Forestier E, Romero-Segura C, Pateraki I, Centeno E, Compagnon V, Preiss M . Distinct triterpene synthases in the laticifers of Euphorbia lathyris. Sci Rep. 2019; 9(1):4840. PMC: 6423090. DOI: 10.1038/s41598-019-40905-y. View

20.

Lepesheva G, Friggeri L, Waterman M . CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology. 2018; 145(14):1820-1836. PMC: 6185833. DOI: 10.1017/S0031182018000562. View