The solution and redox properties of iron that make it the metal prosthetic group of choice for the activation of otherwise kinetically inert substrates, including dioxygen, also make ionic Fe cytotoxic to aerobic organisms. Eukaryotes from yeast to humans have to manage ferrous iron's inherent reactivity with dioxygen and ferric iron's instability in water;the oft-cited role of iron in human pathology from post-ischemic tissue damage to neurodegenerative disease is testament to the importance of managing ionic iron. We propose that the Fe- trafficking pathway that succeeds in suppressing Fe's abiologic side-reactions has three essential elements: ferri-reduction, ferro-oxidation, and iron channeling. Ferric iron is made bioavailable - as FeII - by 1e- reduction with cytoplasmic pyridine nucleotide or dihydroascorbic acid supplying the reducing equivalents via a type 2 membrane protein reductase or, in the case of ascorbate by a direct e--transfer. The pro-oxidant potential of the FeII produced is suppressed by its use as 1e- donor in the 4e- reduction of O2 to 2H2O thus by-passing all 1e- dioxygen reduction products (ROS) in a reaction catalyzed uniquely by a multicopper (MCO) ferroxidase. The FeIII generated in this reaction is shielded from hydrolysis by its direct transfer - its channeling - from ferroxidase to ferric iron binding protein, whether or transport, trafficking or storage. A key component of this metabolic pathway is the ferroxidase. In Project 1 we will continue our productive collaborations which have made major contributions to our understanding of the molecular and electronic bases for the unique reactivity of these copper oxidases. In Projects 2 and 3 we test specific hypotheses about fundamental unknowns in the handling of ionic iron by eukaryotes. Project 2 tests our hypothesis about the Fe-trafficking pathway that couples a ferroxidase reaction to a permeation one in the acquisition of iron by all fungi, including human pathogens. Project 3 will test a model for how reductase, permease and ferroxidase combine to support iron trafficking across the blood brain barrier. Outstanding progress has been made by many groups on the metabolism of Fe-prosthetic groups like heme and Fe/S clusters;ionic Fe is the precurser to these """"""""caged"""""""" Fe- species and is responsible for the """"""""corrosive chemistry"""""""" (Elizabeth Theil) that characterizes the relationship between Fe and dioxygen. An understanding of how cells manage this chemistry would make a significant contribution to our eventual elucidation of the molecular basis for the multitude of human pathologies often attributed in part to mismanaged ionic iron.

Public Health Relevance

In fulfilling their essential need for iron, aerobic organisms like fungi and humans have to rely on biochemical pathways designed to deal with the aqueous and redox chemistry of ionic iron. This chemistry renders iron bio-unavailable and an oxidative threat;iron's contribution to essentially all neurodegenerative diseases is due to this chemistry. This project will provide molecular, mechanistic insight into how ionic iron is managed so as to suppress iron's inherent and potentially cytotoxic reactivity while at the same time be available as an essential co-factor for a multitude of critical cellular activities.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Sechi, Salvatore
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State University of New York at Buffalo
Schools of Medicine
United States
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Ji, Changyi; Steimle, Brittany L; Bailey, Danielle K et al. (2018) The Ferroxidase Hephaestin But Not Amyloid Precursor Protein is Required for Ferroportin-Supported Iron Efflux in Primary Hippocampal Neurons. Cell Mol Neurobiol 38:941-954
Kosman, Daniel J (2018) The teleos of metallo-reduction and metallo-oxidation in eukaryotic iron and copper trafficking. Metallomics 10:370-377
Ji, Changyi; Kosman, Daniel J (2015) Molecular mechanisms of non-transferrin-bound and transferring-bound iron uptake in primary hippocampal neurons. J Neurochem 133:668-83
McCarthy, Ryan C; Kosman, Daniel J (2015) Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier. Front Mol Neurosci 8:31
Bailão, Elisa Flávia L C; Lima, Patrícia de Sousa; Silva-Bailão, Mirelle G et al. (2015) Paracoccidioides spp. ferrous and ferric iron assimilation pathways. Front Microbiol 6:821
McCarthy, Ryan C; Kosman, Daniel J (2015) Iron transport across the blood-brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy. Cell Mol Life Sci 72:709-27
McCarthy, Ryan C; Park, Yun-Hee; Kosman, Daniel J (2014) sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 15:809-15
McCarthy, Ryan C; Kosman, Daniel J (2014) Activation of C6 glioblastoma cell ceruloplasmin expression by neighboring human brain endothelia-derived interleukins in an in vitro blood-brain barrier model system. Cell Commun Signal 12:65
McCarthy, Ryan C; Kosman, Daniel J (2014) Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PLoS One 9:e89003
Kjaergaard, Christian H; Qayyum, Munzarin F; Augustine, Anthony J et al. (2013) Modified reactivity toward O2 in first shell variants of Fet3p: geometric and electronic structure requirements for a functioning trinuclear copper cluster. Biochemistry 52:3702-11

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