Grant: Discovery Grants Program - Individual

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.