Bioinorganic chemistry of porphyrinoids, heme-binding proteins and metallothioneins

金属与许多蛋白质和酶的化学性质密切相关。这种对生命的深远影响使得研究这种化学的各个方面变得至关重要。我们在生物无机化学方面的建议将利用我们最近报道的卟啉、金黄色葡萄球菌的铁摄取和金属硫蛋白的金属化三个重要进展。我们建议：(i)量化环氧化和环还原卟啉的光学和氧化还原性质及其电子结构之间的联系；（ii）利用电喷雾电离质谱法和磁圆二色光谱法研究金黄色葡萄球菌对铁的获取，以阐明和模拟含铁血红素从宿主血红蛋白到细菌细胞内部的完整运输；（iii）使用电喷雾电离质谱法和核磁共振波谱法首次详细描述了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求具有新的、技术要求高的光学和氧化还原特性的设计型卟啉类化合物，以及蛋白质环境与结合铁卟啉状态之间的联系产生重大影响。我们对重要的铁获取途径如何运作的理解将大大增强，因为第一个实时数据显示含铁血红素在体内通过一系列固定在金黄色葡萄球菌壁和膜上的蛋白质进行转移。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，从而了解人类和其他生物中发现的多结构域蛋白进化发展的基本原理。我们的研究跨越了许多传统的界限，需要在免疫学和分子生物学方面的技能，在蛋白质和肽的表达和合成方面的技能，在配位化学和光谱学方面的技能来探测金属基性质，在理论化学方面的技能来进行详细的电子结构建模。通过将具有这些技能的研究人员和合作者聚集在一起，可以理解自然界金属基化学的复杂性。

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.