Bioinorganic chemistry of metalloproteins and tetrapyrroles

金属蛋白和四吡咯的生物无机化学

• 批准号: RGPIN-2020-06545
• 负责人: Stillman, Martin
• 金额: $ 2.62万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717856
• 关键词: Bioinorganic; chemistry; metalloproteins; tetrapyrroles

The foundation of our research programme is the bioinorganic chemistry of metalloproteins and synthetic analogs. Metal-containing proteins dominate Life. A wide range of essential metals fulfill roles from ionic balance, nerve, and muscle action to structural stability (often zinc) to catalytic activity (for example iron). These metals must be inserted into the apoprotein and the structural integrity of the resulting holoprotein assured for optimal, physiological activity. A key cellular aspect is the storage of metals following absorption from nutritional sources. Transition and d-block metals must be bound to chaperones to avoid unwanted and potentially toxic cellular-based reactivity. The metalation pathways, binding constants, reaction mechanisms and the structural impact of metallation on proteins are our focus. These studies are supported by expertise with a wide range of instrumental resources to probe the underlying properties of the biologically demanding molecular systems. Our research makes use of computational data to predict optical and redox properties of the metal-binding sites. Three technologies dominate our studies: (i) Quantitative analytical measurements primarily from equilibrium-, time- and temperature-dependent properties determined by electrospray-ionization mass spectrometry (ESI-MS). (ii) Detailed optical spectroscopic measurements that identify metalated speciation, ligand coordination and spin and oxidation states. (iii) Computational studies of the geometric and electronic structures of complexes involving molecular dynamics for metalloprotein structures and docking, and DFT and TD-DFT methods for coordination geometries and excited state properties. Two classes of metalloprotein and the tetrapyrroles form the core focus of our programme. (i) Proteins that are dependent on metals for activity (specifically, transferrin, heme proteins, carbonic anhydrase, and superoxide dismutase). (ii) Metallothionein, a copper and zinc cellular storage protein that subsequently transfers these metals to metalloenzymes, but in addition this protein scavenges for toxic metals, and, finally, can act as a gate-keeper for the cell, guarding against intrusion by xenobiotic metals (such as metal-containing drugs). Our proposed studies are directly applicable to the protein misfolding currently the focus in catastrophic neurological diseases. We will use computational studies of metal-binding sites to understand the specific chemistries involved during folding. (iii) Tetrapyrroles are the cofactors of heme proteins, and synthetically, as porphyrins and phthalocyanines, offer remarkably diverse properties from the chlorins in chlorophylls, to the porphyrins in the P450 cytochromes and in the oxygen processing apparatus. The synthetic chlorophyll analogs are key to devices that can act as photon collectors in solar cells. Our computationally-guided synthesis will highlight key molecular factors to enhance photosensitizer activity.

我们的研究计划的基础是金属蛋白和合成类似物的生物无机化学。含金属的蛋白质主宰着生命。从离子平衡、神经和肌肉活动到结构稳定性（通常是锌）到催化活性（例如铁），各种必需金属都发挥着重要作用。这些金属必须插入载子蛋白中，并保证所得到的全蛋白的结构完整性，以获得最佳的生理活性。一个关键的细胞方面是从营养来源吸收金属后的储存。过渡金属和d-嵌段金属必须与伴侣结合，以避免不必要的和潜在有毒的细胞反应性。金属化途径、结合常数、反应机制以及金属化对蛋白质的结构影响是我们研究的重点。这些研究得到了广泛的仪器资源的专业知识的支持，以探测生物学上要求很高的分子系统的潜在特性。我们的研究利用计算数据来预测金属结合位点的光学和氧化还原性质。