Mechanism of the Uranyl-Transferrin Complex Formation. Uranium Uptake by Transferrin.

Uranium is a toxic heavy metal, the investigation of its incorporation and transport in biological media is of considerable public health interest. In vitro, uranyl is transferred from one of the major plasma complexes, UO2(CO3)(3)(4-) to Transferrin (T) in four kinetic steps. The first is very fast and accompanied by HCO3- loss. It yields a first intermediate ternary complex between UO2 (CO3)(2)(2-) and the C-lobe of T; k(1): (7.0 +/- 0.4) x 10(5) M-1 s(-1); k(-1) = (4.6 +/- 0.2) x 10(3) M-1 s(-1); K-1 = (6.7 +/- 0.6) x 10(-3). This first kinetic product undertakes a fast rate-limiting conformation change leading to the loss of a second HCO3-: k(2) = (33 +/- 14) s(-1). This second ternary complex undergoes in turn two very slow conformation changes, at the end of which both the C- and N-lobes become loaded with uranyl. When unexposed to uranium, the uranyl concentrations in the bloodstream are much too low to favor receptor-mediated transport. However, in the case of exposure, these concentrations can grow considerably. This added to the fast uranyl complex formation with the C-lobe and the fast interaction of the T(UO2)(2) with the receptor can allow a possible internalization in the cell by the iron-acquisition pathway.