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A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action

View ORCID ProfileJoel Haywood, View ORCID ProfileKaren J. Breese, Jingjing Zhang, View ORCID ProfileMark T. Waters, View ORCID ProfileCharles S. Bond, View ORCID ProfileKeith A. Stubbs, View ORCID ProfileJoshua S. Mylne
doi: https://doi.org/10.1101/2022.04.18.488698
Joel Haywood
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
3Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, Perth 6102, Australia
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  • For correspondence: josh.mylne@curtin.edu.au
Karen J. Breese
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Jingjing Zhang
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Mark T. Waters
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Charles S. Bond
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Keith A. Stubbs
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Joshua S. Mylne
1School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The ARC Centre of Excellence in Plant Energy Biology, University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia
3Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, Perth 6102, Australia
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  • For correspondence: josh.mylne@curtin.edu.au
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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 new 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 enabled the rational design of specific HMGR inhibitors, for which we engineered 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Figure 1, Figure 2, Figure 3, Table 1 revised; Supplemental Figure 5 revised, 3 new supplemental files, 1 new Supplemental Table

  • ↵1 Xing, Y. et al. Efficient Synthesis of the Nucleus of Atorvastatin Calcium. Synthetic Communications 45, 2832-2840 (2015).

  • ↵2 Kawade, R.K. et al. Copper-Catalyzed Aerobic Oxidations of 3-N-Hydoxyaminoprop-1-ynes to Form 3-Substituted 3-Amino-2-en-1-ones: Oxidative Mannich Reactions with a Skeletal Rearrangement. Chemistry - A European Journal 20, 13927-13931 (2014).

  • 3 Boyle, R.G. et al. CHK-1 Inhibitors. PCT Int. Appl. WO 2005028474 A2, 2005.

  • ↵4 Yuan, Y. et al. One-Pot Synthesis of 3-Hydroxyquinolin-2(1H)-ones from N-Phenylacetoacetamide via PhI(OCOCF3)2-Mediated α-Hydroxylation and H2SO4-Promoted Intramolecular Cyclization. Journal of Organic Chemistry 78, 5385-5392 (2013).

  • 5 Xing, Y. et al. Efficient Synthesis of the Nucleus of Atorvastatin Calcium. Synthetic Communications 45, 2832-2840 (2015).

  • ↵6 Naidu, A.A. and Sharma, G.V.R. Synthesis of novel impurities in 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide; an atorvastatin intermediate. Organic Communications 10, 314-322 (2017).

  • ↵7 Sattigeri, J.A. et al. Process for preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt. PCT Int. Appl. WO 2007054790 A1, 2007.

  • ↵8 Estévez, V. et al. Concise synthesis of atorvastatin lactone under high-speed vibration milling conditions. Organic Chemistry Frontiers 1, 458-463 (2014).

  • 9 Sattigeri, J.A. et al. Process for preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt. PCT Int. Appl. WO 2007054790 A1, 2007.

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Posted August 02, 2022.
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A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action
Joel Haywood, Karen J. Breese, Jingjing Zhang, Mark T. Waters, Charles S. Bond, Keith A. Stubbs, Joshua S. Mylne
bioRxiv 2022.04.18.488698; doi: https://doi.org/10.1101/2022.04.18.488698
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A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action
Joel Haywood, Karen J. Breese, Jingjing Zhang, Mark T. Waters, Charles S. Bond, Keith A. Stubbs, Joshua S. Mylne
bioRxiv 2022.04.18.488698; doi: https://doi.org/10.1101/2022.04.18.488698

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