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.
