Hydroxamido vanadates: aqueous chemistry and function in protein tyrosine phosphatases and cell cultures.
The protein tyrosine phosphatases (PTPases) are a group of regulatory enzymes that are critically important to a wide variety of cellular functions. A number of these PTPases have significant potential as targets for therapeutic intervention, for instance, in diabetes and autoimmune disease treatment. The hydroxylamine complex, bis(N,N-dimethylhydroxamido)hydroxooxovanadate (DMHAV), is an excellent inhibitor of the two PTPases, protein tyrosine phosphatase 1B (PTP1B) and leucocyte common antigen related phosphatase (LAR). However, because of the similarity of the active site architecture within the group of known PTPases, DMHAV is probably an effective inhibitor of most PTPases. Information gleaned from studies of the mechanism of inhibition of PTPases by peptide-derived inhibitors, together with information from comparative protein modelling and studies of the aqueous chemistry of DMHAV, 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 glycogen synthesis. Selective PTPase inhibitors that are developed from the basis of the hydroxylamine motif may lead to effective vanadate-based complexes that have potential as therapeutic agents.
Tracey
A S
AS
Department of Chemistry and Institute of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada. tracey@sfu.ca
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D017968:Vanadium Compounds / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007328:Insulin; D017968:Vanadium Compounds; D019000:Phosphotyrosine; D006003:Glycogen; D017027:Protein Tyrosine Phosphatases; D005947:Glucose