A molecular level mechanism for uranium (VI) toxicity through Ca(2+) displacement in pyrroloquinoline quinone-dependent bacterial dehydrogenase.
Dipicolinic acid (DPA), a small molecule analogue for the pyrroloquinoline quinone (PQQ) bacterial dehydrogenase cofactor, was used to model displacement of the complexing ion, Ca(2+), by a uranium (VI) dioxo-cation, UO2(2+). Complexation of UO2(2+) with DPA through the displacement of Ca(2+) was examined with UV/visible spectroscopy, ESI (electrospray ionization)-Mass spectrometry, and density functional theory based-modeling. The UO2(2+) displacement of other biologically important metal cations (Zn(2+), Cu(2+), Ni(2+), and Fe(3+)) from DPA was also examined. Results show that UO2(2+) has a distinctly higher binding affinity (logβ = 10.2 ± 0.1) for DPA compared to that of Ca(2+) (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 UO2(2+) produced significant uranium toxicity in bacteria. The observed toxicity mechanism was determined to be the displacement of a Ca(2+) cation bound to the {ONO} site on PQQ and was observed even at submicromolar UO2(2+) 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 UO2(2+) 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.
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA.
Katherine A
KA
Burbank
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA.
Robert A
RA
Walker
Department of Chemical and Biological Engineering, Montana State University, Bozeman, MT, USA. Electronic address: bpeyton@coe.montana.edu.
Brent M
BM
Peyton
D001426:Bacterial Proteins / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D010088:Oxidoreductases / Q000737:chemistry*; D045542:PQQ Cofactor / Q000737:chemistry*; D010848:Picolinic Acids / Q000737:chemistry; D014501:Uranium / Q000737:chemistry*
D001426:Bacterial Proteins; D056831:Coordination Complexes; D010848:Picolinic Acids; D014501:Uranium; D045542:PQQ Cofactor; D010088:Oxidoreductases; D002118:Calcium; C004860:dipicolinic acid
DFT; Dipicolinic acid; ESI-Mass spectrometry; UV–VIS spectroscopy; Uranyl