KINETICS AND MOLECULAR MODELING STUDIES OF THE INHIBITION OF PROTEIN-TYROSINE PHOSPHATASES BY N,N-DIMETHYLHYDROXYLAMINE COMPLEXES OF VANADIUM(II)

Bis(N,N-dimethylhydroxamido)hydroxooxovanadate and a derivative comple x formed with dithiothreitol have been shown to be excellent inhibitor s of the function of two protein tyrosine phosphatases, leucocyte anti gen related phosphatase (LAR) and protein tyrosine phosphatase-1B (PTP 1B). Inhibition constants of 1.0 +/- 0.3 mu M and 2.3 +/- 0.3 mu M, re spectively, were determined for the inhibition of LAR by the two compl exes. The inhibition of PTP1B is not substantially different. Unlike t he structurally related hydrogen peroxide complexes of vanadium, these complexes inhibit in a fully reversible manner that is consistent wit h a nonoxidative process. Molecular modelling studies suggest the main stabilizing interaction is a cyclic H-bonded structure involving the conserved active site aspartate. Hydrophobic stabilization interaction s were also suggested.