Effectiveness and mode of action of phosphonate inhibitors of plant glutamine synthetase

BACKGROUND: Aiming at the rationale design of new herbicides, the availability of the three-dimensional structure of the target enzyme greatly enhances the optimization of lead compounds and the design of derivatives with increased activity. Among the most widely exploited herbicide targets is glutamine synthetase. Recently, the structure of a cytosolic form of the maize enzyme has been described, allowing verifying whether steric, electronic and hydrophobic features of a compound are in agreement with inhibitor-protein interaction geometry. RESULTS: Three series of compounds (aminophosphonates, hydroxyphosphonates and aminomethylenebisphosphonates) were evaluated as possible inhibitors of maize glutamine synthetase. Aminomethylenebisphosphonate derivatives substituted in the phenyl ring retained the inhibitory potential, whereas variations in the scaffold, i.e. the replacement of the second phosphonate moiety with a hydroxyl or an amino residue, resulted in a significant loss of activity. A kinetic characterization showed a mechanism of non competitive type against glutamate and uncompetitive against ATP. A docking analysis suggested the mode of bisphosphonate binding to the active site. CONCLUSION: Results allowed defining the features required to maintain or enhance the biological activity of these compounds, which represent lead structures to be further exploited for the design of new substances endowed with herbicidal activity.