Theses and Dissertations at Montana State University (MSU)
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Item A molecular basis for uranium toxicity(Montana State University - Bozeman, College of Letters & Science, 2014) Burbank, Katherine Ann; Chairperson, Graduate Committee: Brent M. Peyton; Robert K. Szilagyi was a co-author of the article, 'Development of a computational model to describe U(VI) and Pyrroloquinoline quinone interactions' which is contained within this thesis.; Robert K. Szilagyi and Brent M. Peyton were co-authors of the article, 'The effect of CA 2+ displacement by UO 2 2+ on the biological funtion of methanol dehydrogenase' which is contained within this thesis.; Robert A. Walker and Brent M. Peyton were co-authors of the article, 'A molecular basis of metal toxicity by U(VI) in PQQ dependent bacterial dehydrogenase' which is contained within this thesis.Environmental and health problems associated with uranium extend well beyond its radioactive properties. Hexavelent uranium is a common environmental contaminant that reacts with water to form the dioxo-uranium cation, UO 2 2+. Environmental uranium contamination is the result of a number of activities including uranium mining, production and use of depleted uranium for military purposes, storage and disposal of nuclear weaponry, and fuel for nuclear power plants. Despite the potential importance of the interaction of UO 2 2+ with biologically relevant molecules, only limited molecular insight is available. In a recent publication, the presence of UO 2 2+ in submicromolar concentrations was shown to affect ethanol metabolism in Pseudomonas spp. by displacing the Ca 2+ of the pyrroloquinoline quinone (PQQ) cofactor. Accordingly, the interaction of UO 2 2+ with PQQ is used here as a starting point to carry out both an in vitro and in silico analysis of UO 2 2+ and its interactions with biologically relevant cofactors and metabolites. This work represents a proposed molecular mechanism of uranium toxicity in bacteria, and has relevance for uranium toxicity in many living systems. The structural insights from modeling allow us to expand the scope of potential uranium toxicity to other systems by considering the favorable coordination mode to pyridine nitrogen adjacent to carboxylic and/or carbonyl groups. Consequently, the recent discovery of uranium toxicity at submicromolar levels in bacteria provides relevance to serious environmental and public health issues in the light of current EPA regulation of 0.13 micron uranium limit in drinking water.