Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
School of Health Sciences, Purdue University, West Lafayette, IN 47906, USA.
Molecules. 2021 Feb 22;26(4):1175. doi: 10.3390/molecules26041175.
Manganese (Mn) is a biologically essential metal, critical as a cofactor for numerous enzymes such a glutamine synthetase and kinases such as ataxia-telangiectasia mutated (ATM). Similar to other essential metals such as iron and zinc, proper levels of Mn need to be achieved while simultaneously being careful to avoid excess levels of Mn that can be neurotoxic. A lifetime of occupational exposure to Mn can often lead to a Parkinsonian condition, also known as "manganism", characterized by impaired gait, muscle spasms, and tremors. Despite the importance of its regulation, the mechanisms underlying the transport and homeostasis of Mn are poorly understood. Rather than taking a protein or gene-targeted approach, our lab recently took a high-throughput-screening approach to identify 41 small molecules that could significantly increase or decrease intracellular Mn in a neuronal cell model. Here, we report characterization of these small molecules, which we refer to as the "Mn toolbox". We adapted a Fura-2-based assay for measuring Mn concentration and for measuring relative concentrations of other divalent metals: nickel, copper, cobalt, and zinc. Of these 41 small molecules, we report here the identification of three that selectively influence cellular Mn but do not influence the other divalent metals tested. The patterns of activity across divalent metals and the discovery of Mn-selective small molecules has potential pharmacological and scientific utility.
锰（Mn）是一种必需的生物金属，作为许多酶（如谷氨酰胺合成酶）和激酶（如共济失调毛细血管扩张突变基因（ATM））的辅助因子至关重要。与铁和锌等其他必需金属类似，需要达到适当的 Mn 水平，同时要小心避免过量的 Mn，过量的 Mn 可能具有神经毒性。一生中职业性暴露于 Mn 通常会导致帕金森病，也称为“锰中毒”，其特征为步态障碍、肌肉痉挛和震颤。尽管 Mn 的调节很重要，但 Mn 的运输和体内平衡的机制仍知之甚少。我们的实验室最近没有采用蛋白质或基因靶向方法，而是采用高通量筛选方法来识别 41 种小分子，这些小分子可以在神经元细胞模型中显著增加或减少细胞内 Mn。在这里，我们报告了这些小分子的特性，我们称之为“Mn 工具箱”。我们改编了一种基于 Fura-2 的测定法来测量 Mn 浓度和其他二价金属（镍、铜、钴和锌）的相对浓度。在这 41 种小分子中，我们在此报告了三种能够选择性影响细胞内 Mn 但不影响其他测试的二价金属的小分子的鉴定。这些小分子在各种二价金属中的活性模式以及 Mn 选择性小分子的发现具有潜在的药理学和科学用途。
