Iron, one of the most abundant metals in the biosphere, is a critical nutrient to most biological systems. Due to its characteristic Fe(II) to Fe(III) redox potential iron participates in a wide range of crucial biochemical reactions. Most, if not all organisms have evolved complex iron binding, transport, and storage molecules to maintain iron homeostasis. Microbes manufacture low molecular weight siderophores which bind iron and promote the growth of the organism. In higher animals, iron transport and storage proteins such as transferrin and ferritin have been well characterized. Not well characterized, however, is the intermediate iron transport system between transferrin, ferritin and other sites of iron deposition. Low molecular weight ligands which may fulfill this function in higher animals have been hypothesized but not identified. We have identified and purified a peptide of approximately 1500 molecular weight which displays siderophore activity. This compound, Host Associated Iron Transfer Factor (HAITF), was isolated from mammalian tissue and has been shown to promote growth of gram negative bacteria by an iron transport mechanism. This proposal outlines a plan for further characterizing the chemical nature and metabolic significance of this compound. Studies are designed to determine the primary structure, spectroscopic parameters associated with iron binding and to elucidate the iron binding ligands on the molecule. Metabolic studies are designed to assess any possible role in intracellular iron transport. Finally, studies of HAITF will continue in disease states, associated with abnormal iron homeostasis. This project will not only assess the significance of this compound as an iron transport mechanism, but should provide new insight into the regulation of iron metabolism and mechanisms associated with abnormal iron homeostasis.
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