title: Mechanism of insulin sensitization by BMOV (bis maltolato oxo vanadium); unliganded vanadium (VO4) as the active component.
abstract: Organovanadium compounds have been shown to be insulin sensitizers in vitro and in vivo. One potential biochemical mechanism for insulin sensitization by these compounds is that they inhibit protein tyrosine phosphatases (PTPs) that negatively regulate insulin receptor activation and signaling. In this study, bismaltolato oxovanadium (BMOV), a potent insulin sensitizer, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cells and enhanced insulin receptor activation in vivo. NMR and X-ray crystallographic studies of the interaction of BMOV with two different phosphatases, HCPTPA (human low molecular weight cytoplasmic protein tyrosine phosphatase) and PTP1B (protein tyrosine phosphatase 1B), demonstrated uncomplexed vanadium (VO(4)) in the active site. Taken together, these findings support phosphatase inhibition as a mechanism for insulin sensitization by BMOV and other organovanadium compounds and strongly suggest that uncomplexed vanadium is the active component of these compounds.
authors.affiliation: Procter & Gamble Pharmaceuticals, Cardiovascular Research, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA. peters.kg@pg.com
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Peters
authors.forename: Mike G
authors.initials: MG
authors.lastname: Davis
authors.forename: Brian W
authors.initials: BW
authors.lastname: Howard
authors.forename: Matthew
authors.initials: M
authors.lastname: Pokross
authors.forename: Vinit
authors.initials: V
authors.lastname: Rastogi
authors.forename: Conrad
authors.initials: C
authors.lastname: Diven
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Greis
authors.forename: Elaine
authors.initials: E
authors.lastname: Eby-Wilkens
authors.forename: Matthew
authors.initials: M
authors.lastname: Maier
authors.forename: Artem
authors.initials: A
authors.lastname: Evdokimov
authors.forename: Shari
authors.initials: S
authors.lastname: Soper
authors.forename: Frank
authors.initials: F
authors.lastname: Genbauffe
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D015394:Molecular Structure; D009206:Myocardium / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000819:agonists; D014638:Vanadates / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011518:Proto-Oncogene Proteins; D011753:Pyrones; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D011972:Receptor, Insulin; C490429:ACP1 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516610:Ptpn1 protein, rat