Revision of the Biodistribution of Uranyl in Serum: Is Fetuin-A the Major Protein Target?

Abstract

Uranium is a natural actinide present as uranyl U(VI) species in aqueous environments. Its toxicity is considered to be chemical rather than radiotoxicological. Whatever the route of entry, uranyl reaches the blood, is partly eliminated via the kidneys, and accumulated in the bones. In serum, its speciation mainly involves carbonate and proteins. Direct identification of labile uranyl-protein complexes is extremely difficult because of the complexity of this matrix. Thus, until now the biodistribution of the metal in serum has not been described, and therefore, little is known about the metal transport mechanisms leading to bone accumulation. A rapid screening method based on a surface plasmon resonance (SPR) technique was used to determine the apparent affinities for U(VI) of the major serum proteins. A first biodistribution of uranyl was obtained by ranking the proteins according to the criteria of both their serum concentrations and affinities for this metal. Despite its moderate concentration in serum, fetuin-A (FETUA) was shown to exhibit an apparent affinity within the 30 nM range and to carry more than 80% of the metal. This protein involved in bone mineralization aroused interest in characterizing the U(VI) and FETUA interaction. Using complementary chromatographic and spectroscopic approaches, we demonstrated that the protein can bind 3 U(VI) at different binding sites exhibiting Kd from ∼30 nM to 10 μM. Some structural modifications and functional properties of FETUA upon uranyl complexation were also controlled. To our knowledge, this article presents the first identification of a uranyl carrier involved in bone metabolism along with the characterization of its metal binding sites.

Evidence of isotopic fractionation of natural uranium in cultured human cells

“…Therefore, we can hypothesize the transport of U(VI)-carbonate complexes into cells through the formation of a complex with a transport protein, involving the exchange of carbonate(s) for stronger ligand(s). Indeed, the high affinity of U(VI) for certain proteins has been recently demonstrated (62)(63)(64). Using the total energies of U(VI) compounds reported in literature for theoretical calculations of fractionation factors associated with an NFS effect for the reduction of [UO 2 L 4 ] 2− into UL 4 (65), we performed calculations for ligand exchange reactions in [UO 2 L 4 ] 2− species (L = F − , Cl − , and Br − ).…”

Engineering Short Peptide Sequences for Uranyl Binding

“…Two proteins demonstrated a particularly large affinity for uranyl. Fetuin, despite its low concentration, could be one of the major target proteins of uranyl in the serum,10 and the highly phosphorylated protein osteopontin, involved in the organo‐mineral homeostasis of the bone, also binds tightly with uranyl 11…”

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

“…Although they are known to rapidly circulate and deposit into major organs such as bone, liver, or kidney after contamination (6,(8)(9)(10), the specific molecular mechanisms associated with mammalian uptake of these toxic heavy elements remain largely unexplored. Proposed mammalian actinide acquisition and transport mechanisms have typically focused on proteins that use conserved motifs to directly bind the essential elements iron or calcium (6,8,(10)(11)(12)(13), such as transferrin (14)(15)(16)(17)(18), ferritin (13), osteopontin (19), or fetuin (20). Siderocalin (Scn), an essential antibacterial protein that sequesters iron (21,22), and an important component of iron trafficking (23), is distinct in that it binds ferric iron indirectly, through tight complexes with a siderophore or siderophore-derived chelator.…”