Bellomo Elisa, Birla Singh Kshetrimayum, Massarotti Alberto, Hogstrand Christer, Maret Wolfgang
Metal Metabolism Group, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
Coord Chem Rev. 2016 Nov 15;327-328:70-83. doi: 10.1016/j.ccr.2016.07.002.
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 (Zn) 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 (Zn) 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.
金属生物化学中的一种新范式描述了通过去除金属离子来激活无活性金属酶的过程。蛋白质酪氨酸磷酸酶（PTP）的酶活性似乎不需要金属离子。然而，金属阳离子和金属阴离子都会调节其酶活性。一个结合位点是催化半胱氨酸残基处的磷酸结合位点。与磷酸盐结构相似的氧阴离子，如钒酸盐，以纳摩尔到微摩尔的亲和力抑制该酶。此外，锌离子（Zn）以皮摩尔到纳摩尔的亲和力抑制该酶。我们绘制了靠近阴离子结合位点的阳离子结合位点，并建立了一种仅在酶的封闭构象中发生的特异性抑制机制，此时催化半胱氨酸被磷酸化，催化天冬氨酸移入活性位点。我们在此讨论PTP1B（研究最深入的蛋白质酪氨酸磷酸酶）的阴离子和阳离子双重抑制作用。只有从PTP1B在金属阳离子作为细胞信号离子的生物学背景中的功能来看，这种抑制在磷酸化信号传导中的意义才变得明显。锌离子信号补充氧化还原信号，但由于锌离子对配位环境的特异性和亲和力，在生物时间尺度上提供了不同类型的控制和更持久的抑制。由于PTP1B和其他PTP在健康和疾病，特别是癌症和糖尿病的代谢调节中发挥着重要作用，因此针对它们的抑制剂设计是一个主要的研究领域和热点。我们的结果解释了阳离子（Zn）和氧阴离子如钒酸盐抑制PTP1B并具有胰岛素增强（“抗糖尿病”）作用这一明显的二分法，并提出了不同的方法，即通过影响其生理调节剂来靶向细胞中的PTP，并考虑基于锌和钒化合物的胰岛素增强作用知识的金属药物方法。
