title: Can uranium be transported by the iron-acquisition pathway? Ur uptake by transferrin.
abstract: Transferrin (T) is one of the major protein targets of uranyl (Ur) and the Ur-loaded protein (TUr(2)) interacts with receptor 1. In vitro, Ur is transferred from one of the major plasma complexes, tricarbonated Ur (Ur(CO(3))(3)(4-)) to T in four kinetically differentiated steps. The first is very fast and accompanied by HCO(3)(-) loss. It yields a first intermediate ternary complex between dicarbonated Ur and the phenolate of one of the two tyrosine ligands in the C-lobe; direct rate constant, k(1) = (7.0 ± 0.4) × 10(5) M(-1) s(-1); reverse rate constant, k(-1) = (4.7 ± 0.2) × 10(3) M(-1) s(-1); dissociation constant, K(1) = (6.7 ± 0.6) × 10(-3) and an affinity of the T for the dicarbonated Ur (Ur(CO(3))(2)(2-)) close to that of the latter to CO(3)(2-), K'(3) ~ 1 × 10(4). This first kinetic product undertakes a fast rate-limiting conformation change leading to the loss of a second HCO(3)(-): direct rate constant, k(2) = 33 ± 14 s(-1). This second ternary complex undergoes two very slow conformation changes (1 and 5 h), at the end of which both C- and N-lobes become loaded with Ur. When unexposed to uranium, the Ur 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 Ur complex formation with the C-lobe and the fast interaction of the Ur-loaded T with the receptor, can allow a possible internalization by the iron-acquisition pathway.
authors.affiliation: ITODYS, Interactions, Traitements et Organisation et Dynamique des Systèmes, Université Paris-Diderot, CNRS UMR 7086, 15 rue Jean-Antoine de Baïf, 75205 Paris Cedex 13, France. Hemadi@univ-paris-diderot.fr
authors.forename: Miryana
authors.initials: M
authors.lastname: Hémadi
authors.forename: Nguyêt-Thanh
authors.initials: NT
authors.lastname: Ha-Duong
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: El Hage Chahine
mesh_terms: D001639:Bicarbonates / Q000737:chemistry; D045744:Cell Line, Tumor; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*; D014501:Uranium / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D014168:Transferrin; D014501:Uranium; D007501:Iron