The metal face of protein tyrosine phosphatase 1B☆
| Autor: | E. A. Bellomo, Wolfgang Maret, Kshetrimayum Birla Singh, Christer Hogstrand, Alberto Massarotti |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cation binding biology Chemistry(all) Chemistry Active site Protein tyrosine phosphatase Review 010402 general chemistry 01 natural sciences 3. Good health 0104 chemical sciences Inorganic Chemistry 03 medical and health sciences 030104 developmental biology Biochemistry Materials Chemistry biology.protein Phosphorylation Vanadate Physical and Theoretical Chemistry Binding site Anion binding Cysteine |
| Zdroj: | Coordination Chemistry Reviews Bellomo, E, Singh, K B, Massarotti, A, Hogstrand, C & Maret, W 2016, ' The Metal Face of Protein Tyrosine Phosphatase 1B ', COORDINATION CHEMISTRY REVIEWS, vol. 327-328, pp. 70-83 . https://doi.org/10.1016/j.ccr.2016.07.002 |
| ISSN: | 0010-8545 |
| Popis: | Highlights • Modulation of phosphatase activity by metal cations and metal oxyanions. • Zinc inhibition of protein tyrosine phosphatase 1B. • Structural chemistry of inhibitory metal sites in proteins. • Metal buffering in enzymatic assays. A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn2+) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn2+) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing (“anti-diabetic”) effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds. |
| Databáze: | OpenAIRE |
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