Lahiani Adi, Yavin Ephraim, Lazarovici Philip
School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, P.O.Box 12065, Jerusalem 91120, Israel.
Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Toxins (Basel). 2017 Mar 16;9(3):107. doi: 10.3390/toxins9030107.
An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as , and the modulation of the different signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A₂ (PLA₂) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.
了解微生物、植物或动物分泌的毒素发挥作用的分子机制，是评估人类健康风险的最重要因素，并为使用毒素模拟剂治疗从神经疾病到癌症等多种病症开辟了新的思路。最近，分子和细胞生物学剖析工具提供了大量关于这些不同毒素作用的信息，然而，仍缺乏一个综合框架来解释它们的选择性毒性。在这篇综述中，强调了不同毒素的具体例子，以说明在不同生化、分子和细胞水平上的基本毒性机制，并特别考虑了神经系统。主要作用靶点已被突出显示并在操作上分为13个子类别。将选定的毒素例子分配到每个靶点类别中，命名为 ，并介绍了不同信号传导的调节。第一个门户包括质膜脂质结构域，例如当受到鱼类毒素豹蟾鱼毒素的攻击时，它会形成孔道，或者当脂质代谢酶如磷脂酶A₂（PLA₂）或磷脂酶C（PLC）作用于它时，它会发生降解。几个主要门户由离子通道、泵、转运体和配体门控离子型受体组成，许多毒素作用于这些部位，扰乱细胞内离子稳态。另一组门户由G蛋白偶联受体和酪氨酸激酶受体组成，它们在与特定毒素相互作用后，会将第二信使改变到病理水平。最后，亚细胞器如线粒体、细胞核、蛋白质和RNA合成机制、细胞骨架网络和胞吐小泡也是其他多种毒素靶向和失调的门户。从这些看似不同的毒素在作用位点以及它们在宿主中触发的第二信使和信号级联反应方面，可以得出一个基本概念。虽然与初始门户的相互作用在很大程度上由毒素的化学性质决定，但一旦进入细胞，几种普遍存在的第二信使和蛋白激酶/磷酸酶途径就会受损，从而导致毒性。因此，毒素是开发选择性靶向参与人类生理和疾病的主要细胞门户的新型疗法最有前景的天然分子之一。
