Grant: Discovery Grants Program - Individual

<p>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.<br /> 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.</p>