Recognition- and reactivity-based fluorescent probes for studying transition metal signaling in living systems.
Recognition- and reactivity-based fluorescent probes for studying transition metal signaling in living systems.
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DOI：
10.1021/acs.accounts.5b00221
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发表时间：
2015-08-18
影响因子：
18.3
通讯作者：
Chang CJ
中科院分区：
文献类型：
--
作者：
Aron AT;Ramos-Torres KM;Cotruvo JA Jr;Chang CJ
金属对于生命至关重要，在生物学中心教条的各个方面都发挥着关键作用（例如，核酸的转录和翻译以及蛋白质的合成）。氧化还原非活性的碱金属、碱土金属和过渡金属（例如钠、钾、钙和锌）被广泛认为是动态信号，而氧化还原活性的过渡金属（例如铜和铁）传统上被认为被蛋白质配体螯合，包括作为静态酶辅因子，部分原因是它们有可能通过芬顿化学引发氧化应激和损伤。生物学中的金属可以大致分为两类：静态和不稳定。在前者中，蛋白质和其他大分子与金属紧密结合;在后者中，金属与细胞配体（包括蛋白质和低分子量配体）的结合相对较弱。荧光探针可以是研究过渡金属在其不稳定形式中的作用的有用工具。用于成像生命系统中过渡金属动力学的探针必须满足几个严格的标准。除了表现出理想的生物物理特性和生物相容性，它们必须是选择性的，并显示出对感兴趣的金属的荧光开启响应。为了应对这一挑战，我们采用了两种金属检测的一般策略，称为“识别”和“反应性”。我们的过渡金属探针设计采用了铜和镍的基于还原的方法以及钴和铁的基于反应性的方法。本报告总结了本实验室在荧光探针的开发和应用方面的进展，以识别和研究过渡金属在生物学中的信号作用。与直接金属检测和遗传和/或药理学操作的补充方法相结合，过渡金属的荧光探针有助于揭示过渡金属动力学的一些基本原理。在这个帐户中，我们给出了三个最近的例子，从我们的实验室和合作中，化学探针的应用表明，不稳定的铜有助于各种生理。第一个例子表明，铜是一种内源性调节神经元的活动，第二个说明细胞的线粒体铜稳态的优先顺序，第三个确定的“铜小体”作为一个新的铜存储室莱茵衣藻绿色藻类。事实上，识别和反应性为基础的荧光探针已经帮助发现新的生物学作用的不稳定的过渡金属，和荧光探针的进一步发展，包括不同的Kd值和新的反应触发器和识别受体，将继续揭示令人兴奋的和新的生物学作用的不稳定的过渡金属。
Metals are essential for life, playing critical roles in all aspects of the central dogma of biology (e.g., the transcription and translation of nucleic acids and synthesis of proteins). Redox-inactive alkali, alkaline earth, and transition metals such as sodium, potassium, calcium, and zinc are widely recognized as dynamic signals, whereas redox-active transition metals such as copper and iron are traditionally thought of as sequestered by protein ligands, including as static enzyme cofactors, in part because of their potential to trigger oxidative stress and damage via Fenton chemistry. Metals in biology can be broadly categorized into two pools: static and labile. In the former, proteins and other macromolecules tightly bind metals; in the latter, metals are bound relatively weakly to cellular ligands, including proteins and low molecular weight ligands. Fluorescent probes can be useful tools for studying the roles of transition metals in their labile forms. Probes for imaging transition metal dynamics in living systems must meet several stringent criteria. In addition to exhibiting desirable photophysical properties and biocompatibility, they must be selective and show a fluorescence turn-on response to the metal of interest. To meet this challenge, we have pursued two general strategies for metal detection, termed “recognition” and “reactivity”. Our design of transition metal probes makes use of a recognition-based approach for copper and nickel and a reactivity-based approach for cobalt and iron. This Account summarizes progress in our laboratory on both the development and application of fluorescent probes to identify and study the signaling roles of transition metals in biology. In conjunction with complementary methods for direct metal detection and genetic and/or pharmacological manipulations, fluorescent probes for transition metals have helped reveal a number of principles underlying transition metal dynamics. In this Account, we give three recent examples from our laboratory and collaborations in which applications of chemical probes reveal that labile copper contributes to various physiologies. The first example shows that copper is an endogenous regulator of neuronal activity, the second illustrates cellular prioritization of mitochondrial copper homeostasis, and the third identifies the “cuprosome” as a new copper storage compartment in Chlamydomonas reinhardtii green algae. Indeed, recognition- and reactivity-based fluorescent probes have helped to uncover new biological roles for labile transition metals, and the further development of fluorescent probes, including ones with varied Kd values and new reaction triggers and recognition receptors, will continue to reveal exciting and new biological roles for labile transition metals.