A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action

Joel Haywood (), Karen J. Breese, Jingjing Zhang, Mark T. Waters, Charles S. Bond, Keith A. Stubbs and Joshua S. Mylne ()
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Joel Haywood: Curtin University, Bentley
Karen J. Breese: The University of Western Australia
Jingjing Zhang: The University of Western Australia
Mark T. Waters: The University of Western Australia
Charles S. Bond: The University of Western Australia
Keith A. Stubbs: The University of Western Australia
Joshua S. Mylne: Curtin University, Bentley

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Decades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a mode of action target for the development of herbicides. Here, we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enables the rational design of specific HMGR inhibitors and we develop a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.

Date: 2022
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DOI: 10.1038/s41467-022-33185-0

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