A Molecular Level Mechanism for Uranium(VI) Toxicity Through Ca2+ Displacement in Pyrroloquinoline Quinone Dependent Bacterial Dehydrogenase
- Burbank, Katherine A. [ Montana State University: Chemistry & Biochemistry ]
- Walker, Robert A. [ Montana State University: Chemistry & Biochemistry ]
- Peyton, Brent M. [ Montana State University: Chemical & Biological Engineering ]
Dipicolinic acid (DPA), a small molecule analogue for the pyrroloquinoline quinone (PQQ) bacterial dehydrogenase cofactor, was used to model displacement of the complexing ion, Ca2 +, by a uranium(VI) dioxo-cation, UO22 +. Complexation of UO22 + with DPA through the displacement of Ca2 + was examined with UV/Visible spectroscopy, ESI-mass spectrometry, and density functional theory based-modeling. The UO22 + displacement of other biologically important metal cations (Zn2 +, Cu2 +, Ni2 +, and Fe3 +) from DPA was also examined. Results show that UO22 + has a distinctly higher binding affinity (logβ = 10.2 ± 0.1) for DPA compared to that of Ca2 + (logβ = 4.6 ± 0.1), and provide molecular level insight into the mechanism of uranium toxicity associated with the {ONO} site. These results support those of VanEngelen et al. (2011) where a key interaction between PQQ and UO22 + produced significant uranium toxicity in bacteria. The observed toxicity mechanism was determined to be the displacement of a Ca2 + cation bound to the {ONO} site on PQQ and was observed even at submicromolar UO22 + concentrations. Here we couple experimental findings with density functional theory (DFT) calculations to investigate the electronic and structural properties that make the {ONO} site so distinctively favorable for UO22 + binding. This novel approach using integrated experimental and fundamental atomic based models opens the path to identify a library of potential uranium interactions with critical biological molecules.