New Target Enzyme(s) for Bisphosphonates: Inhibition of Geranylgeranyl Diphosphate Synthase

Abstract

Bisphosphonates, exemplified by CGA 103586 (Patent of Nissan; U.S., 4,447,256; Germany, 28 31 578), are a class of herbicides with excellent activity after stem injection. Theirin vivoactivity is weak due to uptake problems of compounds containing to highly polar phosphonate moieties. The mode of action of bisphosphonates was until now controversial. Our results clearly show that a group of bisphosphonates inhibit the chlorophyll- and carotenoid-biosynthesis pathways by blocking geranylgeranyl diphosphate synthase without interfering with the shikimate pathway as previously published. Besides this main effect the bisphosphonates examined in this study inhibit to a lesser extent squalene synthase and phytoene synthase which is not critical for herbicidal activity. The unique enzyme inhibition pattern reported here constitutes, to our knowledge, a new mode of action.