Singh Kshetrimayum Birla, Maret Wolfgang
Department of Zoology, Pachhunga University College, Mizoram University, Aizawl, 796001, Mizoram, India.
Metal Metabolism Group, Department of Biochemistry, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
Biometals. 2017 Aug;30(4):517-527. doi: 10.1007/s10534-017-0019-9. Epub 2017 May 24.
Protein tyrosine phosphatases are not considered to be metalloenzymes. Yet, they are inhibited by zinc cations and metal and non-metal oxyanions that are chemical analogues of phosphate, e.g. vanadate. Metal inhibition is generally not recognized as these enzymes are purified, supplied, and assayed with buffers containing chelating and reducing agents. We screened a series of cations and anions for their capacity to inhibit protein tyrosine phosphatase 1B and discuss the ensuing general issues with inhibition constants reported in the scientific literature. In contrast to zinc, which binds to the phosphocysteine intermediate in the closed conformation of protein tyrosine phosphatase 1B when the catalytic aspartate has moved into the active site, other divalent cations such as cadmium and copper may also bind to the enzyme in the open conformation. Inhibition by both anions and cations, conditions such as pH, the presence of metal ligands such as glutathione, and the existence of multiple conformational states of protein tyrosine phosphatases in the reaction cycle establish a complex pattern of inhibition of these important regulatory enzymes with implications for the physiology, pharmacology and toxicology of metal ions.
蛋白质酪氨酸磷酸酶不被认为是金属酶。然而，它们会受到锌阳离子以及与磷酸盐化学结构类似的金属和非金属含氧阴离子（如钒酸盐）的抑制。由于这些酶在含有螯合剂和还原剂的缓冲液中进行纯化、供应和检测，金属抑制作用通常未被认识到。我们筛选了一系列阳离子和阴离子抑制蛋白质酪氨酸磷酸酶1B的能力，并讨论了科学文献中报道的抑制常数所引发的一般问题。与锌不同，当催化天冬氨酸移入活性位点时，锌会在蛋白质酪氨酸磷酸酶1B的封闭构象中与磷酸半胱氨酸中间体结合，而其他二价阳离子如镉和铜可能也会在开放构象中与该酶结合。阴离子和阳离子的抑制作用、诸如pH值等条件、诸如谷胱甘肽等金属配体的存在以及反应循环中蛋白质酪氨酸磷酸酶多种构象状态的存在，都建立了一种复杂的对这些重要调节酶的抑制模式，这对金属离子的生理学、药理学和毒理学具有重要意义。
