The roles of iron and cadmium in human health

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dc.contributor Vincent, John B.
dc.contributor Cassady, Carolyn J.
dc.contributor Shaughnessy, Kevin H.
dc.contributor Duffy, Carol
dc.contributor.advisor Busenlehner, Laura S. Wang, Yu 2017-03-01T16:59:00Z 2017-03-01T16:59:00Z 2014
dc.identifier.other u0015_0000001_0001514
dc.identifier.other Wang_alatus_0004D_11868
dc.description Electronic Thesis or Dissertation
dc.description.abstract The trace transition metals in humans are divided into two groups, the essential metals and the non-essential/non-native heavy metals. This dissertation research explores the interactions of two transition metals, iron and cadmium, with protein targets to understand their effects on human health. Iron is an important essential metal and is a component of two inorganic cofactors, heme and Fe/S clusters. Disruption of heme and Fe/S cluster cofactor assembly causes downstream protein dysfunction, oxidative stress, and cellular damage. Many diseases, such as the neurodegenerative disease Friedreich's ataxia (FRDA), are caused by the inability to synthesize Fe/S clusters. FRDA is the result of decreased expression of the mitochondrial protein frataxin; however, its exact function is unclear. In this dissertation, a Schizosaccharomyces pombe fission yeast strain was generated in which the yeast frataxin homologue fxn1 was overexpressed to determine what the function(s) of frataxin is through the affected pathways. Based on this study, we demonstrated that S. pombe Fxn1 overexpression elevated the activities of Fe/S enzymes through the up-regulation of Fe/S cluster synthesis, which led to imbalanced iron metabolism, mitochondrial dysfunction and oxidative stress. This research supports that mitochondrial Fxn1 up-regulates the efficiency of Fe/S cluster assembly and provides insight into the cause of FRDA. Besides diseases caused by dysregulation of essential metals, there are diseases related to chronic exposure to heavy metals. The heavy metal cadmium is linked to breast cancers, but with unknown mechanisms. One proposed mechanism is that Cd<super>2+</super> activates the estrogen receptor &alpha (hER&alpha;) transcriptional regulator by binding to the protein and mimicking the conformational effects of the hormone estrogen. We utilized hydrogen/deuterium exchange mass spectrometry to analyze the structural changes of the hER&alpha; ligand binding domain upon estradiol or Cd<super>2+</super> binding. Estradiol binding leads to conformational changes in the dimer interface, the estradiol binding cavity, and the loop between helix H11 and H12. Cadmium demonstrated similar conformational changes at the dimer interface and helix H12. This is the first direct evidence that hER&alpha; LBD undergoes structural changes upon Cd<super>2+</super> binding that are similar to that caused by hormone binding, lending support for this potential mechanism of Cd<super>2+</super>-induced carcinogenesis.
dc.format.extent 155 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.ispartof The University of Alabama Libraries Digital Collections
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Biochemistry
dc.subject.other Biophysics
dc.title The roles of iron and cadmium in human health
dc.type thesis
dc.type text University of Alabama. Dept. of Chemistry Chemistry The University of Alabama doctoral Ph.D.

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