School of Chemistry and Molecular Biology, University of Queensland, Brisbane 4072, Australia
In order to maintain a reliable supply of food for the world's increasing population herbicides must play a continued and crucial role. One leading class of herbicides are those that act as inhibitors of acetohydroxyacid synthase, the first enzyme in the branched chain amino acid biosynthesis pathway. However, there are concerns for their continued use due to target site resistance. It is therefore crucial that new advances in herbicide development be made. Here, we clarify the mechanism of inhibition of two chemical classes of AHAS inhibitors (i.e.sulfonylureas and triazolopyrimidines) reconciling ambiguities in the literature that have stood for over thirty years. This study explains how these compounds trigger accumulative inhibition of AHAS, a feature that accounts for their exceptional potency. We also show that the mechanism of inhibition involves the subversion of the inherent oxygenate side-reaction of AHAS, leading to the oxidative inactivation of the enzyme.