Uranium is a natural element widely found in the environment, due to both natural occurrence in mineral ores or in sea water and industrial applications. The production of nuclear energy uses enriched uranium in
235U for nuclear fission. Despite its ubiquitous distribution, uranium has no essential role in living organisms and presents radiological and chemical toxicities. Despite significant recent advances in the field, there is still a serious lack of knowledge about the molecular interactions responsible for uranium toxicity. The underlying mechanisms need to be unraveled to predict the effect of uranium on living organisms and also to help in designing efficient detoxification agents, to be used in case of dirty bombs or accidental release of uranium in the environment.
At the CIBEST lab, we propose a biomimetic approach to help understanding the interactions of uranium with biological molecules, relevant to uranium toxicity. The most stable uranium ion
in vivo is the uranyl cation, UO22+, which prefers four to six oxygen donors in its equatorial plane, perpendicular to O-U-O bonds. We use short peptide sequences, as simple models of metal-binding sites in proteins to get structural and thermodynamic data, which are not accessible directly with large biological molecules. Cyclic constrained peptide scaffolds that orient metal-coordinating groups found in proteins toward the equatorial plan of the uranyl cation revealed to be highly effective uranyl-binding peptides.
A combination of synthesis, analytical chemistry, X-Absorption Spectroscopy and theoretical calculations allowed us to correlate the amino acid sequence to the stability of the uranyl complexes. Importantly, phosphate groups significantly enhance the affinity of the biomimetic peptides for uranyl, which strongly supports the importance of phosphoamino acids in uranyl binding in proteins. Therefore, our biomimetic approach reinforces the relevance of considering phosphoproteins such as osteopontin as potential uranyl targets
in vivo.
This work was supported by the toxicology and NRBC programs of CEA.