Inhibition of acyl‐ACP thioesterase as site of action of the commercial herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam

Inhibition of acyl‐ACP thioesterase as site of action of the commercial herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam

BACKGROUND Understanding the mode and site of action of a herbicide is key for its efficient development, the evaluation of its toxicological risk, efficient weed control and resistance management. Recently, the mode of action (MoA) of the herbicide cinmethylin was identified in lipid biosynthesis w...

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Published in:Pest management science Vol. 78; no. 8; pp. 3620 - 3629
Main Authors: Johnen, Philipp, Zimmermann, Sophie, Betz, Michael, Hendriks, Janneke, Zimmermann, Alexandra, Marnet, Martina, De, Inessa, Zimmermann, Gunther, Kibat, Christine, Cornaciu, Irina, Mariaule, Vincent, Pica, Andrea, Clavel, Damien, Márquez, José Antonio, Witschel, Matthias
Format: Journal Article
Language:English
Published: Chichester, UK John Wiley & Sons, Ltd 01-08-2022
Wiley Subscription Services, Inc
Subjects:
Binding
Biosynthesis
Cereal crops
crop protection
Crystal structure
Crystallization
Enzymatic activity
FAT inhibition
herbicide
Herbicides
Inhibitors
Lipids
Metabolism
Mode of action
pest management
Risk management
site of action
Thioesterase
Weed control
Weeds
herbicide
FAT inhibition
pest management
mode of action
crop protection
site of action
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Summary:BACKGROUND Understanding the mode and site of action of a herbicide is key for its efficient development, the evaluation of its toxicological risk, efficient weed control and resistance management. Recently, the mode of action (MoA) of the herbicide cinmethylin was identified in lipid biosynthesis with acyl‐ACP thioesterase (FAT) as the site of action (SoA). Cinmethylin was registered for selective use in cereal crops for the control of grass weeds in 2020. RESULTS Here, we present a high‐resolution co‐crystal structure of FAT in complex with cumyluron identified by a high throughput crystallization screen. We show binding to and inhibition of FAT by cumyluron. Furthermore, in an array of experiments consisting of FAT binding assays, FAT inhibition assays, physiological and metabolic profiling, we tested compounds that are structurally related to cumyluron and identified the commercial herbicides oxaziclomefone, methyldymron, tebutam and bromobutide, with so far unknown sites of action, as FAT inhibitors. Additionally, we show that the previously described FAT inhibitors cinmethylin and methiozolin bind to FAT in a nanomolar range, inhibit FAT enzymatic activity and lead to similar metabolic changes. CONCLUSION Based on presented data, we corroborate cinmethylin and methiozolin as potent FAT inhibitors and identify FAT as the SoA of the herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam. © 2022 Society of Chemical Industry. Using a combination of structural biology, biochemistry, plant physiology and metabolomics, we identify inhibition of fatty acid thioesterase (FAT) as Mode of Action (MoA) for the commercial herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam, and corroborate FAT inhibition as MoA for cinmethylin and methiozolin.
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ISSN:1526-498X
1526-4998
DOI:10.1002/ps.7004