This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hard X-ray XAS studies will be conducted on metalloproteins, metal-based drugs, genotoxic species of relevance to metal-induced cancers, and other bioinorganic systems. Heme protein studies will be conducted, in which Fe K-edge investigations will be focused on the binding of small molecules to the heme, in order to understand the factors that influence whether such binding is used as a switch in a biological function, or to transport (or store) the small molecule. K-edge Cr XAS studies will be used to determine the structures of frozen solutions of reactive Cr(VI), Cr(V) and Cr(IV) species of relevance to Cr-induced cancers. Many of these species are too reactive to be crystallized and can only be generated as transients in solution. Similarly, Cr(III) complexes are used as dietary supplements and potential anti-diabetics, but the active species are poorly characterized. XAFS will be used to characterize intermediates with biomolecules that are thought to be relevant to the biotransformations of such dietary supplements. The binding of metal ions to melanin is an important way in which melanoma cells prevent metal ions from leading to cell death, because melanoma cells contain relatively high intracellular concentration of H2O2 that reacts with metal ions to lead to toxins that would kill the cells and hence prevent the growth of melanomas. Hence are investigating the binding of metals ions to melanin and their roles in forming melanin from L-dopa using K-edge XAFS. Finally, we are investigating the structures of Cu, Ni and Zn anti-inflammatory drugs in pharmaceutical preparations and artificial gastric juices in order to understand how the structure of the complexes affects their efficacy and side-effects. By understanding their stabilities and structures in different formulations and their biotransformations in simulated gastric juices, we will optimize pharmaceutical formulations and gain a better understanding of the pharmacology of these drugs.
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