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Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance

Schwarz, Maria; Eno, Rebecca F.M.; Freitag-Pohl, Stefanie; Coxon, Christopher R.; Straker, Hannah E.; Wortley, David J.; Hughes, David J.; Mitchell, Glynn; Moore, Jenny; Cummins, Ian; Onkokesung, Nawaporn; Brazier-Hicks, Melissa; Edwards, Robert; Pohl, Ehmke; Steel, Patrick G.

Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance Thumbnail


Authors

Maria Schwarz

Rebecca F.M. Eno

Christopher R. Coxon

Hannah E. Straker

David J. Wortley

David J. Hughes

Glynn Mitchell

Jenny Moore

Ian Cummins

Nawaporn Onkokesung

Melissa Brazier-Hicks

Robert Edwards



Abstract

The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione-S-transferase (AmGSTF1) as a functional biomarker of MHR in black-grass (Alopecurus myosuroides). This study provides further insights into the role of AmGSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type AmGSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the AmGSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of AmGSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to AmGSTF1 was investigated showing a high affinity for derivatives bearing a O-5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds.

Citation

Schwarz, M., Eno, R. F., Freitag-Pohl, S., Coxon, C. R., Straker, H. E., Wortley, D. J., …Steel, P. G. (2021). Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance. Organic and Biomolecular Chemistry, 19(42), 9211-9222. https://doi.org/10.1039/d1ob01802g

Journal Article Type Article
Acceptance Date Sep 30, 2021
Online Publication Date Oct 13, 2021
Publication Date Nov 14, 2021
Deposit Date Oct 19, 2021
Publicly Available Date Jan 10, 2022
Journal Organic & Biomolecular Chemistry
Print ISSN 1477-0520
Electronic ISSN 1477-0539
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 19
Issue 42
Pages 9211-9222
DOI https://doi.org/10.1039/d1ob01802g

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