Bioinorganic chemistry of metalloproteins and synthetic analogues

金属蛋白和合成类似物的生物无机化学

• 批准号: RGPIN-2015-05819
• 负责人: Stillman, Martin
• 金额: $ 4.3万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=690856
• 关键词: Bioinorganic; chemistry; metalloproteins; synthetic; analogues

The research to be carried out concerns the biological functionality of metals and their host molecules, and the prediction of properties for technological applications of synthetic analogues. Metals in biological systems control all life, in many cases by binding to the donor atoms of amino acids in the peptide chains of proteins. Metal ions also bind to specific chelators that then activate proteins for function. Metals are the active site for catalysis, maintain cellular ionic strength, form structural materials and control protein folding through their coordination to amino acids. While all organisms require a variety of metals, the supply and availability of these metal ions must be regulated in the cell to avoid deficiency, leading to functional stress, while an excess leads to toxicity.***Our program has three long term goals. First, to understand the role of the protein metallothionein in the metabolic pathways of zinc and copper, and also the role of metallothionein as a `cellular gate-keeper' deactivating metal-based drugs as they enter the cell. Second, to describe in detail how the fascinatingly complicated process of heme acquisition and transfer works in a range of gram-negative and gram-positive pathogenic bacteria. Bacteria require iron but for human pathogenic bacteria the host environment is almost devoid of free iron. These microbes thus employ a combination of strategies to scavenge for iron. One method in the human host is to rip the iron-containing heme out of hemoglobin and transport it whole to the inside of the bacterium cell where the iron is extracted. This system involves protein to protein handovers of a complete heme, as it is moves across the cell wall and through the cell membrane. Third, to determine the geometrical control of the optical and redox properties of porphyrinoids from theoretically-obtained electronic structures. This work concerns the spectacular optical and redox properties of porphyrins and their analogs. Porphyrins are responsible for plant life through the magnesium chlorophyll, and as well many porphyrin-based proteins. These biological properties can be exploited technologically but Nature has had 3 billion years to refine the chemistry. Modified porphyrins are hard to synthesize and their photo-optic and redox properties become known only then. The productivity enhancements arising from predictions of the properties of molecular structures prior to synthesis will lead to faster commercial exploitation. The planned research utilizes the spectroscopic techniques typically used for these metal-based studies (optical absorption and emission, magnetic circular dichroism, metal-based NMR, and synchrotron-based EXAFS) to understand reactivities discovered using electrospray ionization spectrometry.**

将进行的研究涉及金属及其主体分子的生物功能，以及合成类似物技术应用的性能预测。生物系统中的金属控制着所有的生命，在许多情况下是通过与蛋白质肽链中氨基酸的供体原子结合来控制的。金属离子也结合到特定的螯合剂，然后激活蛋白质的功能。金属是催化的活性位点，通过与氨基酸配位来维持细胞离子强度，形成结构材料并控制蛋白质折叠。虽然所有生物体都需要各种金属，但这些金属离子的供应和可用性必须在细胞中进行调节，以避免缺乏导致功能应激，而过量则导致毒性。我们的计划有三个长期目标。首先，了解金属硫蛋白在锌和铜的代谢途径中的作用，以及金属硫蛋白作为“细胞守门人”在金属药物进入细胞时使其失活的作用。第二，详细描述血红素的获取和转移是如何在一系列革兰氏阴性和革兰氏阳性致病菌中进行的。细菌需要铁，但对人类致病菌来说，宿主环境几乎没有游离铁。因此，这些微生物采用了一种组合策略来补充铁。在人类宿主中的一种方法是将含铁血红素从血红蛋白中分离出来，并将其整体运输到细菌细胞内部，在那里提取铁。该系统涉及一个完整血红素的蛋白质到蛋白质的转换，因为它穿过细胞壁并穿过细胞膜。第三，从理论上获得的电子结构确定卟啉类化合物的光学和氧化还原性质的几何控制。这项工作涉及卟啉及其类似物的壮观的光学和氧化还原性质。卟啉通过镁叶绿素和许多卟啉基蛋白质负责植物生命。这些生物特性可以通过技术加以利用，但大自然有30亿年的时间来完善化学。改性卟啉很难合成，只有到那时才知道它们的光电和氧化还原性质。在合成之前预测分子结构的性质所产生的生产率提高将导致更快的商业开发。计划中的研究利用通常用于这些基于金属的研究的光谱技术（光学吸收和发射，磁性圆二色性，基于金属的NMR和基于同步加速器的EXAFS）来理解使用电喷雾电离光谱法发现的反应性。