The Discovery of a Novel Site of Action for Herbicidal Bisphosphonates

Following renewed interest in a class of herbicides containing a 1,1-bisphosphonate moiety, studies to identify the molecular target for these compounds were initiated. N-(2-(3-methylpyridyl)) aminomethylene diphosphonic acid (compound I), a representative example of this group, was found not to inhibit soluble plant pyrophosphatases or H+-translocating pyrophosphatases in the vacuolar membrane. Fatty acid biosynthesis from acetate or from pyruvate was also not suppressed by this herbicide. Germination of plant seeds was not inhibited by the bisphosphonate, but root growth in the dark was strongly inhibited without a significant effect on respiration. The bisphosphonate had little effect on nucleic acid biosynthesis. However, the biosynthesis of carotenoids from isopentenyl pyrophosphate in daffodil (Narcissus sp.) chromoplasts was found to be strongly inhibited by compound I at 2.5 µM. Further study showed that isopentenyl pyrophosphate:dimethylallylpyrophosphate isomerase was not blocked by the compound but that farnesyl pyrophosphate synthase was very strongly inhibited by compound I with an IC50of 23 nM. It is proposed that bisphosphonates such as compound I are herbicidal as a result of the inhibition of farnesyl pyrophosphate synthase in the prenyl biosynthetic pathway and that this enzyme represents a new target site for the development of herbicides. Copyright 1999 Academic Press.