Chalcone-based Selective Inhibitors of a C(4) Plant Key Enzyme as Novel Potential Herbicides

Weeds are a challenge for global food production due to their rapidly evolving resistance against herbicides. We have identified chalcones as selective inhibitors of phosphoenolpyruvate carboxylase (PEPC), a key enzyme for carbon fixation and biomass increase in the C(4) photosynthetic pathway of many of the world’s most damaging weeds. In contrast, many of the most important crop plants use C(3) photosynthesis. Here, we show that 2′,3′,4′,3,4-Pentahydroxychalcone (IC(50) = 600 nM) and 2′,3′,4′-Trihydroxychalcone (IC(50) = 4.2 μM) are potent inhibitors of C(4) PEPC but do not affect C(3) PEPC at a same concentration range (selectivity factor: 15–45). Binding and modeling studies indicate that the active compounds bind at the same site as malate/aspartate, the natural feedback inhibitors of the C(4) pathway. At the whole plant level, both substances showed pronounced growth-inhibitory effects on the C(4) weed Amaranthus retroflexus, while there were no measurable effects on oilseed rape, a C(3) plant. Growth of selected soil bacteria was not affected by these substances. Our chalcone compounds are the most potent and selective C(4) PEPC inhibitors known to date. They offer a novel approach to combat C(4) weeds based on a hitherto unexplored mode of allosteric inhibition of a C(4) plant key enzyme.