highlight / actuality
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. 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.
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.
Starck M, Laporte FA, Oros S, Sisommay N, Gathu V, Solari PL, Creff G, Roques J, Den Auwer C, Lebrun C and Delangle P
Cyclic phosphopeptides to rationalize the role of phosphoamino acids in uranyl binding to biological targets.
Chemistry-A-European Journal, 2017, 23(22): 5281-5290
Starck M, Sisommay N, Laporte FA, Oros S, Lebrun C and Delangle P
Preorganized peptide scaffolds as mimics of phosphorylated proteins binding sites with a high affinity for uranyl.
Inorganic Chemistry, 2015, 54(23): 11557-11562
Lebrun C, Starck M, Gathu V, Chenavier Y and Delangle P
Engineering short peptide sequences for uranyl binding.
Chemistry-A-European Journal, 2014, 20(50): 16566-16573
Thesis presented Octobre 10, 2017 by Fanny Laporte. PhD thesis available as a pdf file.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.