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

DOI: 10.1039/D1OB01802G DOI Help

Authors: Maria Schwarz (University of Durham) , Rebecca F. M. Eno (University of Durham) , Stefanie Freitag-Pohl (University of Durham) , Christopher R. Coxon (University of Durham) , Hannah E. Straker (University of Durham) , David J. Wortley (University of York) , David J. Hughes (Syngenta) , Glynn Mitchell (Syngenta) , Jenny Moore (Syngenta) , Ian Cummins (University of Durham) , Nawaporn Onkokesung (University of Durham) , Melissa Brazier-Hicks (Newcastle University) , Robert Edwards (Newcastle University) , Ehmke Pohl (Newcastle University) , Patrick G. Steel (University of Durham)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Organic & Biomolecular Chemistry , VOL 19 , PAGES 9211 - 9222

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 24948

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 20/04/2022 12:03


Discipline Tags:

Plant science Earth Sciences & Environment Biochemistry Agriculture & Fisheries Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)