Investigating the Molecular Basis of Uranium Toxicity

A depleted form of high-valent uranium (U(IV)) is a common environmental contaminant that in aqueous environments forms the highly mobile dioxouranium or uranyl cation, UO₂²⁺ [1]. A recent work proposed that the presence of uranyl in micromolar concentrations can seriously hinder ethanol metabolism in Pseudomonas bacteria by displacing the Ca²⁺ cation of the pyrroloquinoline quinone (PQQ) cofactor [2].  This UO₂²⁺/PQQ interaction was used as a starting point to carry out an in vitro analysis of the coordination preference of simplified PQQ models for Ca²⁺ versus UO₂²⁺ binding.

We started with dipicolinic acid, for it contains all the required anchoring points seen on the site where UO₂²⁺ displaces of Ca²⁺ ions on PQQ. Additionally, we inquired as to whether the UO­₂²⁺ ion can displace Zn²⁺, Cu²⁺, and Ni²⁺ ions, all of which have biological relevance. We confirmed that displacement does occur for all cations using UV/Vis Spectroscopy and ESI-Mass Spectrometry. To further this study, we limited the coordination environment using picolinic acid. A systematic UV/vis spectroscopic analysis was preformed on solutions containing 10 mM picolinic acid. The cations used previously were added in equimolar concentrations to separate picolinic acid solutions. Subsequently, equimolar concentrations of uranyl was added as UO₂(NO₃)₂. We have identified competitive UO₂²⁺ displacement for this ligand as well.

With these results, we have defined the minimal binding motif and we can now initiate database searches to identify cofactors and metabolites along with their biological role that have potential in showing UO₂²⁺ binding and related chemical toxicity.