Iron present in loosely bound or unchelated forms within cells can act catalytically to produce DNA damaging and lipid peroxidizing oxygen radicals. Oxidative damage of cells is now thought to be causally related to many widespread human diseases including arthritis, atherosclerosis, cancer and cellular aging. An understanding of the mechanisms by which organisms regulate uptake of iron and store intracellular iron is central to an understanding of the etiology of these diseases as well as infectious disease. The ability of microbial pathogens to acquire iron from the host is an important component of virulence. While much progress has been made in determining the molecular details of iron uptake in procaryotes, a comparable description in eucaryotes is lacking. This proposal addresses the molecular analysis of a genetically accessible, eucaryotic iron assimilation system. The siderophore-mediated high affinity iron transport system of Ustilago maydis, the cause of corn smut disease, will be studied. The molecular mechanism of biosynthesis of the siderophore ferrichrome will be delineated by molecular and genetic analysis of the genes controlling ferrichrome biogenesis and by isolating and characterizing the products specified by these genes. The phytopathogenicity and survival of U. maydis mutants unable to produce siderophores will also be investigated. These studies will provide the first molecular description of a siderophore biosynthetic pathway in a eucaryotic organism and provide information on the biologic role of siderophores in the life cycle of this fungus.
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