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.

Beyond iron: non-classical biological functions of bacterial siderophores

“…Plutonium can bind transferrin and enter mammalian cells via the ferric transferrin uptake machinery. 167 The interplay between plutonium and microorganisms has also been investigated. Desferrioxamine (DFO) siderophores display high affinity for Pu(IV); 168 for Pu(IV)-DFOB, log β 110 = 30.8 and Pu(IV)-DFOE is sufficiently stable that its crystal structure was determined using X-ray diffraction methods (Figure 5).…”

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.…”

Is DTPA a good competing chelating agent for Th(IV) in human serum and suitable in targeted alpha therapy?

“…The increase of complexation can be relatively well reproduced till a carbonate concentration of 10 [28,31]. It is worth saying that the absence of complexation between Th(IV) and transferrin observed by Jeanson et al [15] is certainly due to a kinetic problem; Th and HSTf were contacted only for a few hours. Several parameters may explain these differences between Th(IV) and Fe(III) binding.…”

“…Furthermore, one recent study showed no interaction between Th(IV) and HSTf [15], these results being rather conflicting with the others.…”

“…To complex Th(IV), a synergistic anion was therefore considered in the present work, starting with the NTA, the one used by Harris et al and Jeanson et al in previous studies [12,15]. The second one corresponds to carbonate, CO 3 2-being the synergistic anion allowing the complexation with iron and other metal ions [21].…”