In:
Organic & Biomolecular Chemistry, Royal Society of Chemistry (RSC), Vol. 19, No. 42 ( 2021), p. 9211-9222
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 ( Am GSTF1) as a functional biomarker of MHR in black-grass ( Alopecurus myosuroides ). This study provides further insights into the role of Am GSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type Am GSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the Am GSTF1 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 Am GSTF1, 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 Am GSTF1 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.
Type of Medium:
Online Resource
ISSN:
1477-0520
,
1477-0539
Language:
English
Publisher:
Royal Society of Chemistry (RSC)
Publication Date:
2021
detail.hit.zdb_id:
2097583-1
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