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The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity

Pinneh, E.C.; Mina, J.G.; Stark, M.J.R.; Lindell, S.D.; Luemmen, P.; Knight, M.R.; Steel, P.G.; Denny, P.W.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity Thumbnail


Authors

E.C. Pinneh

J.G. Mina

M.J.R. Stark

S.D. Lindell

P. Luemmen

P.G. Steel



Abstract

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, AtIPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for AtIPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.

Citation

Pinneh, E., Mina, J., Stark, M., Lindell, S., Luemmen, P., Knight, M., …Denny, P. (2019). The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Scientific Reports, 9, Article 8083. https://doi.org/10.1038/s41598-019-44544-1

Journal Article Type Article
Acceptance Date May 21, 2019
Online Publication Date May 30, 2019
Publication Date May 31, 2019
Deposit Date Dec 13, 2018
Publicly Available Date May 30, 2019
Journal Scientific Reports
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 9
Article Number 8083
DOI https://doi.org/10.1038/s41598-019-44544-1
Public URL https://durham-repository.worktribe.com/output/1311751

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http://creativecommons.org/licenses/by/4.0/

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copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2019.






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