The impact of the contamination of living organisms by actinide elements has been a constant subject of attention since the 1950s. But to date still little is understood. Ferritin is the major storage and regulation protein of iron in many organisms, it consists of a protein ring and a ferrihydric core at the center. This work sheds light on the interactions of early actinides (Th, Pu) at oxidation state +IV with ferritin and its ability to store those elements at physiological pH compared to Fe. The ferritin–thorium load curve suggests that ThIV saturates the protein (2840 Th atoms per ferritin) in a similar way that Fe does on the protein ring. Complementary spectroscopic techniques (spectrophotometry, infrared spectroscopy, and X‐ray absorption spectroscopy) were combined with molecular dynamics to provide a structural model of the interaction of ThIV and PuIV with ferritin. Comparison of spectroscopic data together with MD calculations suggests that ThIV and PuIV are complexed mainly on the protein ring and not on the ferrihydric core. Indeed from XAS data, there is no evidence of Fe neighbors in the Th and Pu environments. On the other hand, carboxylates from amino acids of the protein ring and a possible additional carbonate anion are shaping the cation coordination spheres. This thorough description from a molecular view point of ThIV and PuIV interaction with ferritin, an essential iron storage protein, is a cornerstone in comprehensive nuclear toxicology.
Since the early 40s when the first research related to the development of the atomic bomb began for the Manhattan Project, actinides (An) and their association with the use of nuclear energy for civil applications, such as in the generation of electricity, have been a constant source of interest and fear. In 1962, the first Society of Toxicology (SOT), led by H. Hodge, was established at the University of Rochester (USA). It was commissioned as part of the Manhattan Project to assess the impact of nuclear weapons production on workers’ health. As a result of this initiative, the retention and excretion rates of radioactive heavy metals, their physiological impact in the event of acute exposure and their main biological targets were assessed. In this context, the scientific community began to focus on the role of proteins in the transportation and in vivo accumulation of An. The first studies focused on the identification of these proteins. Thereafter, the continuous development of physico-chemical characterization techniques has made it possible to go further and specify the modes of interaction with proteins from both a thermodynamic and structural point of view, as well as from the point of view of their biological activity. This article reviews the work performed in this area since the Manhattan Project. It is divided into three parts: first, the identification of the most affine proteins; second, the study of the affinity and structure of protein-An complexes; and third, the impact of actinide ligation on protein conformation and function.
Ferritin is the main protein of Fe storage in eukaryote and prokaryote cells. It is a large multifunctional, multi-subunit protein consisting of heavy H and light L subunits. In the field of nuclear toxicology, it has been suggested that some actinide elements, such as thorium and plutonium at oxidation state +IV, have a comparable `biochemistry' to iron at oxidation state +III owing to their very high tendency for hydrolysis and somewhat comparable ionic radii. Therefore, the possible mechanisms of interaction of such actinide elements with the Fe storage protein is a fundamental question of bio-actinidic chemistry. We recently described the complexation of Pu(IV) and Th(IV) with horse spleen ferritin (composed mainly of L subunits). In this article, we bring another viewpoint to this question by further combining modeling with our previous EXAFS data for Pu(IV) and Th(IV). As a result, the interaction between the L subunits and both actinides appears to be non-specific but driven only by the density of the presence of Asp and Glu residues on the protein shell. The formation of an oxyhydroxide Th or Pu core has not been observed under the experimental conditions here, nor the interaction of Th or Pu with the ferric oxyhydroxide core.
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