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

Elizabeth C. Pinneh, John G. Mina, Michael J.R. Stark, Stephen D. Lindell, Peter Luemmen, Marc R. Knight, Patrick G. Steel, Paul W. Denny

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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.

Original languageEnglish
Article number8083
JournalScientific Reports
Volume9
Issue number1
Early online date30 May 2019
DOIs
Publication statusPublished - 1 Dec 2019

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Herbicides
Inositol
Yeasts
Arabidopsis
Enzymes
Sphingolipids
Enzyme Assays
Seedlings
Libraries
Protein Isoforms

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Pinneh, Elizabeth C. ; Mina, John G. ; Stark, Michael J.R. ; Lindell, Stephen D. ; Luemmen, Peter ; Knight, Marc R. ; Steel, Patrick G. ; Denny, Paul W. / The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. / Pinneh, Elizabeth C.; Mina, John G.; Stark, Michael J.R.; Lindell, Stephen D.; Luemmen, Peter; Knight, Marc R.; Steel, Patrick G.; Denny, Paul W.

In: Scientific Reports, Vol. 9, No. 1, 8083, 01.12.2019.

Research output: Contribution to journalArticle

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