The roles of iron and cadmium in human health

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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 Cd2+ activates the estrogen receptor &alpha (hERα) 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 hERα ligand binding domain upon estradiol or Cd2+ 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 hERα LBD undergoes structural changes upon Cd2+ binding that are similar to that caused by hormone binding, lending support for this potential mechanism of Cd2+-induced carcinogenesis.

Electronic Thesis or Dissertation
Biochemistry, Biophysics