Inhibition of Protein Tyrosine Phosphatase

An interesting facet of the molecular modelling studies [66] was that they suggested that one methyl group of the hydroxylamine ligand was in an orientation suitable for replacement by other functionality. This is potentially important because PTPase active site residues are highly conserved, and enzyme selectivity is conferred 

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Hydrogen peroxide (H202) exhibits insulin-like activity in isolated cells. Like that of vanadate, this effect is thought to be mediated by inhibition of protein-tyrosine phosphatases. 

Trodusquemine (221) (isolated from the liver of the dogfish shark, Squalus acanthias) Sulfated aminosterol Trodusquemine (MSI-1436) (221) Diabetes Suppresses mammalian appetite through inhibition of protein tyrosine phosphatase IB (PTP-IB) Phase I (against type 2 diabetes and related symptoms) Genaera Corporation 974-978... 

Huyer, G., S. Liu, J. Kelly, J. Moffat, P. Payette, B. Kennedy, G. Tsaprailis, M.J. Gresser, and C. Ramachandran. 1997. Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272 843-851. 

Cuncic, C., S. Desmarais, N. Detich, A.S. Tracey, MJ. Gresser, and C. Ramachandran. 1999. Bis(N,N-dimethylhydroxamido)hydroxooxovanadate inhibition of protein tyrosine phosphatase activity in intact cells Comparison with vanadate. Biochem. Pharmacol. 58 1859-1867. 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

Huyer, G. 1997. Mechanism of inhibition of protein tyrosine phosphatases by vanadate and pervanadate. J. Biolog. Chem. 272 843-851. 

Nxumalo, F., N.R. Glover, and A.S. Tracey. 1998. Kinetics and molecular modelhng studies of the inhibition of protein tyrosine phosphatases by N,N-dimethylhydroxy-lamine complexes of vanadium(V). Journal of Biological Inorg. Chem. 3 534—542. 

Inhibitory Inhibition of protein tyrosine phosphatase-IB by glutathionylation [15]... 

Wiesmann C, Barr KJ, Rung J et al (2004) Allosteric inhibition of protein tyrosine phosphatase IB. Nat Struct Mol Biol 11 730—737... 

Asante-Appiah E, Patel S, Desponts C et al (2006) Conformation-assisted inhibition of protein-tyrosine phosphatase-IB elicits inhibitor selectivity over T-ceU protein-tyrosine phosphatase. J Biol Chem 281 8010-8015... 

Chemical Inhibition of Protein Tyrosine Phosphatase Activity... 

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