title: Picomolar concentrations of free zinc(II) ions regulate receptor protein-tyrosine phosphatase β activity.
abstract: As key enzymes in the regulation of biological phosphorylations, protein-tyrosine phosphatases are central to the control of cellular signaling and metabolism. Zinc(II) ions are known to inhibit these enzymes, but the physiological significance of this inhibition has remained elusive. Employing metal buffering for strict metal control and performing a kinetic analysis, we now demonstrate that zinc(II) ions are reversible inhibitors of the cytoplasmic catalytic domain of the receptor protein-tyrosine phosphatase β (also known as vascular endothelial protein-tyrosine phosphatase). The K(i)((Zn)) value is 21 ± 7 pm, 6 orders of magnitude lower than zinc inhibition reported previously for this enzyme. It exceeds the affinity of the most potent synthetic small molecule inhibitors targeting these enzymes. Inhibition is in the range of cellular zinc(II) ion concentrations, suggesting that zinc regulates this enzyme, which is involved in vascular physiology and angiogenesis. Thus, for some enzymes that are not recognized as zinc metalloenzymes, zinc binding inhibits rather than activates as in classical zinc enzymes. Activation then requires removal of the inhibitory zinc.
authors.affiliation: Division of Diabetes and Nutritional Sciences, School of Medicine, King's College London, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilson
authors.forename: Christer
authors.initials: C
authors.lastname: Hogstrand
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maret
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D017434:Protein Structure, Tertiary; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D015032:Zinc