The role of transferrin in actinide(IV) uptake: comparison with iron(III).
ABSTRACT The impact of actinides on living organisms has been the subject of numerous studies since the 1950s. From a general point of view, these studies show that actinides are chemical poisons as well as radiological hazards. Actinides in plasma are assumed to be mainly complexed to transferrin, the iron carrier protein. This paper casts light on the uptake of actinides(IV) (thorium, neptunium, plutonium) by transferrin, focusing on the pH dependence of the interaction and on a molecular description of the cation binding site in the protein. Their behavior is compared with that of iron(III), the endogenous transferrin cation, from a structural point of view. Complementary spectroscopic techniques (UV/Vis spectrophotometry, microfiltration coupled with gamma spectrometry, and X-ray absorption fine structure) have been combined in order to propose a structural model for the actinide-binding site in transferrin. Comparison of our results with data available on holotransferrin suggests some similarities between the behavior of Fe(III) and Np(IV)/Pu(IV)/ Np(IV) is not complexed at pH <7, whereas at pH approximately 7.4 complexation can be regarded as quantitative. This pH effect is consistent with the in vivo transferrin "cycle". Pu(IV) also appears to be quantitatively bound by apotransferrin at around pH approximately 7.5, whereas Th(IV) was never complexed under our experimental conditions. EXAFS data at the actinide edge have allowed a structural model of the actinide binding site to be elaborated: at least one tyrosine residue could participate in the actinide coordination sphere (two for iron), forming a mixed hydroxo-transferrin complex in which actinides are bound with transferrin both through An-tyrosine and through An--OH bonds. A description of interatomic distances is provided.
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ABSTRACT: Although the formation of tetravalent plutonium (Pu(IV)) polymers with natural organic matter was previously observed by spectroscopy, there is no quantitative evidence of such reaction in batch experiments. In the present study, Pu(IV) interaction with humic acid (HA) was investigated at pH 1.8, 2.5 and 3, as a function of HA concentration and for Pu total concentration equal to 6 × 10−8 M. The finally measured Pu(IV) concentrations ([Pu(IV)]eq) are below Pu(IV) solubility limit. Pu(IV)–HA interaction can be explained by the complexation of Pu(IV) monomers by HA up to [Pu(IV)]eq ∼ 10−8 M. However, the slope of the log–log Pu(IV)–HA binding isotherm changes from ∼0.7 to ∼3.5 for higher [Pu(IV)]eq than ∼10−8 M and at any pH. This result suggests the stabilization of hydrolyzed polymeric Pu(IV) species by HA, with a 4:1 Pu:HA stoichiometry. This confirms, for the first time, previous observations made by spectroscopy in concentrated systems. The humic-ion binding model, Model VII, was introduced into the geochemical speciation program PHREEQC and was used to simulate Pu(IV) monomers binding to HA. The simulations are consistent with other tetravalent actinides–HA binding data from literature. The stabilization of a Pu tetramer (Pu4(OH)88+) by HA was proposed to illustrate the present experimental results for [Pu(IV)]eq > 10−8 M. Predictive simulations of Pu(IV) apparent solubility due to HA show that the chosen Pu(IV)-polymer has no impact for pH > 4. However, the comparison between these predictions and recent spectroscopic results suggest that more hydrolyzed polymeric Pu(IV) species can be stabilized by HA at pH > 4. Polymeric Pu(IV)–HA species might significantly enhance Pu(IV) apparent solubility due to humics, which support a colloid-facilitated transport of this low solubility element.Geochimica et Cosmochimica Acta 04/2014; 131:290–300. · 4.25 Impact Factor
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ABSTRACT: Following an internal contamination event, the transport of actinide (An) and lanthanide (Ln) metal ions through the body is facilitated by endogenous ligands such as the human iron-transport protein transferrin (Tf). The recognition of resulting metallo-transferrin complexes (M2Tf) by the cognate transferrin receptor (TfR) is therefore a critical step for cellular uptake of these metal ions. A high performance liquid chromatography-based method has been used to probe the binding of M2Tf with TfR, yielding a direct measurement of the successive thermodynamic constants that correspond to the dissociation of TfR(M2Tf)2 and TfR(M2Tf) complexes for Fe3+, Ga3+, La3+, Nd3+, Gd3+, Yb3+, Lu3+, 232Th4+, 238UO22+, and 242Pu4+. Important features of this method are (i) its ability to distinguish both 1 : 1 and 1 : 2 complexes formed between the receptor and the metal-bound transferrin, and (ii) the requirement for very small amounts of each binding partner (<1 nmol of protein per assay). Consistent with previous reports, the strongest receptor affinity is found for Fe2Tf (Kd1 = 5 nM and Kd2 = 20 nM), while the lowest affinity was measured for Pu2Tf (Kd1 = 0.28 μM and Kd2 = 1.8 μM) binding to the TfR. Other toxic metal ions such as ThIV and UVI, when bound to Tf, are well recognized by the TfR. Under the described experimental conditions, the relative stabilities of TfR:(MxTf)y adducts follow the order Fe3+ ≫ Th4+ ∼ UO22+ ∼ Cm3+ > Ln3+ ∼ Ga3+ ⋙ Yb3+ ∼ Pu4+. This study substantiates a role for Tf in binding lanthanide fission products and actinides, and transporting them into cells by receptor-mediated endocytosis.Metallomics 02/2013; · 4.10 Impact Factor
- Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor