Abstract
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. The first statins to market have also been shown to be herbicidal yet their development as herbicides has been hindered by the risk of off-target effects. Here we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) that exhibits a wider active site than all know structures from non-plant species. This enabled the rational design of statin derivatives with plant-specificity. By sequence analysis of natural statin fungal gene clusters, we could also engineer statin-resistant transgenic plants. These results suggest HMGR is a viable herbicide target, modifiable to provide a tolerance trait.
Competing Interest Statement
The authors have declared no competing interest.