A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals

Rugen, Michael D., Vernet, Mathieu M. J. L., Hantouti, Laila, Soenens, Amalia, Andriotis, Vasilios M. E., Rejzek, Martin, Brett, Paul, van den Berg, Richard J. B. H. N., Aerts, Johannes M. F. G., Overkleeft, Hermen S. and Field, Robert A. ORCID: https://orcid.org/0000-0001-8574-0275 (2018) A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals. Scientific Reports, 8 (1). ISSN 2045-2322

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Abstract

Iminosugars are carbohydrate mimics that are useful as molecular probes to dissect metabolism in plants. To analyse the effects of iminosugar derivatives on germination and seedling growth, we screened a library of 390 N-substituted iminosugar analogues against Arabidopsis and the small cereal Eragrostis tef (Tef). The most potent compound identified in both systems, N-5-(adamantane-1-yl-ethoxy)pentyl- l-ido-deoxynojirimycin (l-ido-AEP-DNJ), inhibited root growth in agar plate assays by 92% and 96% in Arabidopsis and Tef respectively, at 10 µM concentration. Phenocopying the effect of l-ido-AEP-DNJ with the commercial inhibitor (PDMP) implicated glucosylceramide synthase as the target responsible for root growth inhibition. l-ido-AEP-DNJ was twenty-fold more potent than PDMP. Liquid chromatography-mass spectrometry (LC-MS) analysis of ceramide:glucosylceramide ratios in inhibitor-treated Arabidopsis seedlings showed a decrease in the relative quantity of the latter, confirming that glucosylceramide synthesis is perturbed in inhibitor-treated plants. Bioinformatic analysis of glucosylceramide synthase indicates gene conservation across higher plants. Previous T-DNA insertional inactivation of glucosylceramide synthase in Arabidopsis caused seedling lethality, indicating a role in growth and development. The compounds identified herein represent chemical alternatives that can overcome issues caused by genetic intervention. These inhibitors offer the potential to dissect the roles of glucosylceramides in polyploid crop species.

Item Type:	Article
Additional Information:	Funding Information: This work was supported by a Biotechnology and Biological Sciences Research Council (BBSRC, UK) Institute Strategic Programme Grant (MET) [BB/J004561/1] to the John Innes Centre, a BBSRC-Crop Improvement Research Club (CIRC) grant BB/I017291/1 to R.A.F. and BBSRC PhD studentship BB/J500069/1 to M.D.R.
Uncontrolled Keywords:	general ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	04 Sep 2024 08:33
Last Modified:	25 Sep 2024 18:05
URI:	https://ueaeprints.uea.ac.uk/id/eprint/96497
DOI:	10.1038/s41598-018-34749-1

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