Bioinorganic chemistry of porphyrinoids, heme-binding proteins and metallothioneins

类卟啉、血红素结合蛋白和金属硫蛋白的生物无机化学

• 批准号: 37-2010
• 负责人: Stillman, Martin
• 金额: $ 3.64万
• 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: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=512963
• 关键词: Bioinorganic; chemistry; porphyrinoids; heme; binding

Metals are intimately connected with the chemistry of many proteins and enzymes. This far reaching impact on life makes it vitally important for all facets of this chemistry to be studied. Our proposal in bioinorganic chemistry will exploit three important advances concerning porphyrins, iron-uptake by Staphylococcus aureus, and metallation of metallothioneins that we have recently reported. We propose: (i) to quantify the connection between the optical and redox properties of ring oxidized and ring reduced porphyrinoids and their electronic structures; (ii) study iron acquisition by S. aureus bacteria using electrospray ionization mass spectrometry and magnetic circular dichroism spectroscopy to elucidate and model the complete trafficking of the iron-containing heme from the host's hemoglobin to inside the bacterial cell; (iii) use electrospray ionization mass spectrometry and NMR spectroscopy to provide the first detailed description of the metallation reactions of the ubiquitous, metal-binding protein, metallothionein. Our work in these three areas will have significant impact on the quest for designer-porphyrinoids that exhibit new, technologically-demanding optical and redox properties, and on the connection between the protein environment and status of bound iron-porphyrins. Our understanding of how an important iron-acquisition pathway operates will be dramatically enhanced by the first real-time data showing iron-containing heme transfer across a series of proteins that are, in vivo, immobilized in the S. aureus wall and membrane. Finally, our studies of metallothionein will unravel the secrets of its metal binding pathways leading to an understanding of the rationale for the evolutionary development of the multiple domain proteins found in humans and other organisms. Our research crosses many traditional boundaries and calls for skills in immunology and molecular biology, in biochemistry for the expression and synthesis of proteins and peptides, in coordination chemistry and spectroscopy to probe the metal-based properties, and in theoretical chemistry for the detailed electronic structure modeling. By assembling researchers and collaborators together with these skills, the complexity of Nature's metal-based chemistry can be understood.

金属与许多蛋白质和酶的化学成分密切相关。这种对生命的深远影响使得研究这种化学的方方面面变得至关重要。我们在生物无机化学方面的建议将利用我们最近报道的关于卟啉、金黄色葡萄球菌对铁的吸收和金属硫蛋白的金属化的三个重要进展。我们建议：(I)量化环氧化和环还原的卟啉类化合物的光学和氧化还原性质与其电子结构之间的关系；(Ii)使用电喷雾电离质谱学和磁圆二色谱研究金黄色葡萄球菌对铁的获取，以阐明和模拟含铁的血红素从宿主的血红蛋白到细菌细胞内的完整运输；(Iii)使用电喷雾电离质谱仪和核磁共振光谱来首次详细描述无处不在的金属结合蛋白金属硫蛋白的金属化反应。我们在这三个领域的工作将对寻找具有新的、技术要求高的光学和氧化还原性能的设计者-卟啉类化合物产生重大影响，并对蛋白质环境和结合的铁卟啉的状态之间的联系产生重大影响。第一个实时数据显示含铁的血红素通过一系列蛋白质转移，这些蛋白质在体内固定在金黄色葡萄球菌的壁和膜上，这将极大地提高我们对重要的铁获取途径如何运作的理解。最后，我们对金属硫蛋白的研究将揭开其金属结合途径的秘密，从而了解在人类和其他生物中发现的多结构域蛋白质进化发展的基本原理。我们的研究跨越了许多传统的界限，需要免疫学和分子生物学的技能，蛋白质和多肽的表达和合成的生物化学技能，探索金属性质的配位化学和光谱学技能，以及详细的电子结构建模的理论化学技能。通过将研究人员和合作者与这些技能结合在一起，可以理解自然界基于金属的化学的复杂性。