Hydroxamido vanadates: aqueous chemistry and function in protein tyrosine phosphatases and cell cultures

The protein tyrosine phosphatases (PTPases) are a group of regulatory enzym es that are critically important to a wide variety of cellular functions. A number of these PTPases have significant, potential as targets for therape utic intervention, for instance, in diabetes and autoimmune disease treatme nt. The hydroxylamine complex, bis(N,N-dimethylhydroxamido)hydroxooxovanada te (DMHAV), is an excellent inhibitor of the two PTPases, protein tyrosine phosphatase 1B (PTP1B) and leucocyte common antigen related phosphatase (LA R). However, because of the similarity of the active site architecture with in the group of known PTPases, DMHAV is probably an effective inhibitor of most PTPases. Information gleaned from studies of the mechanism of inhibiti on of PTPases by peptide-derived inhibitors, together with information from comparative protein modelling and studies of the aqueous chemistry of DMHA V, has provided insights for the development of selective PTPase inhibitors . In cell cultures, DMHAV is effective in increasing phosphotyrosine levels on the insulin receptor and greatly facilitates glucose transport and glyc ogen synthesis. Selective PTPase inhibitors that are developed from the bas is of the hydroxylamine motif may lead to effective vanadate-based complexe s that have potential as therapeutic agents. (C) 2000 Published by Elsevier Science Inc. All rights reserved.