Vanadium-phosphatase Complexes: Phosphatase Inhibitors Favor the Trigonal Bipyramidal Transition State Geometries

Abstract Over the past two decades increasing information about the function and structural detail of phosphatases has become available detailing the interaction with vanadate or other vanadium compounds. Considering the importance of the phosphorylation reaction in signal transductions the structural details of the interaction of vanadate or other vanadium species with many phosphatases are used to provide information on the nature of successful inhibitors of these enzymes. Analysis shows that most of the available X-ray structures of vanadium–phosphatase complexes contain vanadium with five coordinating atoms in trigonal bipyramidal coordination geometries even though corresponding small molecule analog compounds may have square pyramidal geometries. This finding for the static structures in their solid state documents the fact that the variety of phosphatases all stabilize a vanadium geometry that is closer to the trigonal bipyramidal geometry than square pyramidal geometry. We also review the efficacy of vanadium-based inhibitors and examine both oxometalates and vanadium coordination complexes. The evaluation of the inhibitory efficacies of the oxometalates provides the opportunity to identify product-based inhibitors and transition-state-based inhibitors. Whether initial coordination geometry is important to inhibitor design geometry was examined. For vanadium–phosphatase complexes, regardless of what form was added to the protein crystal in all but one case vanadate was found bound in the phosphatase. Because of speciation considerations and prior hydrolysis of potential vanadium complexes, this result may be a consequence of the experimental conditions. With regard to inhibition we find that the coordination geometry of the starting complex does not need to be trigonal bipyramidal to result in a effective phosphatase inhibitor and that all reported phosphatase inhibitors span a range of only three orders of magnitude in K i across all phosphatases examined.