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 (Lead / Corresponding author), Paul W. Denny (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    32 Downloads (Pure)

    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
    Pages (from-to)1-8
    Number of pages8
    JournalScientific Reports
    Volume9
    DOIs
    Publication statusPublished - 30 May 2019

    Fingerprint

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

    Cite this

    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. pp. 1-8.
    @article{199e37b7ffe246779794249bf9e729db,
    title = "The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity",
    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.",
    author = "Pinneh, {Elizabeth C.} and Mina, {John G.} and Stark, {Michael J. R.} and Lindell, {Stephen D.} and Peter Luemmen and Knight, {Marc R.} and Steel, {Patrick G.} and Denny, {Paul W.}",
    note = "E.C.P. was supported by a Biotechnology and Biological Research Council CASE studentship with Bayer Crop Sciences (BB/K012703/1). J.G.M. and P.W.D. were also supported by the Biotechnology and Biological Research Council (BB/M024156/1); P.W.D. and P.G.S. are also supported by the Medical Research Council (MR/P027989/1). We thank Durham University’s Wolfson Research Institute for Health and Wellbeing, and Biophysical Sciences Institute for support.",
    year = "2019",
    month = "5",
    day = "30",
    doi = "10.1038/s41598-019-44544-1",
    language = "English",
    volume = "9",
    pages = "1--8",
    journal = "Scientific Reports",
    issn = "2045-2322",
    publisher = "Nature Publishing Group",

    }

    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. (Lead / Corresponding author); Denny, Paul W. (Lead / Corresponding author).

    In: Scientific Reports, Vol. 9, 8083, 30.05.2019, p. 1-8.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity

    AU - Pinneh, Elizabeth C.

    AU - Mina, John G.

    AU - Stark, Michael J. R.

    AU - Lindell, Stephen D.

    AU - Luemmen, Peter

    AU - Knight, Marc R.

    AU - Steel, Patrick G.

    AU - Denny, Paul W.

    N1 - E.C.P. was supported by a Biotechnology and Biological Research Council CASE studentship with Bayer Crop Sciences (BB/K012703/1). J.G.M. and P.W.D. were also supported by the Biotechnology and Biological Research Council (BB/M024156/1); P.W.D. and P.G.S. are also supported by the Medical Research Council (MR/P027989/1). We thank Durham University’s Wolfson Research Institute for Health and Wellbeing, and Biophysical Sciences Institute for support.

    PY - 2019/5/30

    Y1 - 2019/5/30

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85066487185&partnerID=8YFLogxK

    U2 - 10.1038/s41598-019-44544-1

    DO - 10.1038/s41598-019-44544-1

    M3 - Article

    C2 - 31147620

    VL - 9

    SP - 1

    EP - 8

    JO - Scientific Reports

    JF - Scientific Reports

    SN - 2045-2322

    M1 - 8083

    ER -