“…It remains an open question as to whether reduction of the iron(III) in the endosome occurs prior to dissociation from Tf in the Fe 2 -Tf/TfR assembly, or subsequent to dissociation from Tf. A redox-mediated release of iron from transferrin is an attractive hypothesis because the binding constant of transferrin with Fe(II) is 17 orders of magnitude lower than that with Fe (III), and Fe(II) exchanges its first coordination shell at a much faster rate than Fe(III) [5,6]. When bound to the receptor, Fe 2 -Tf has a reduction potential of −300 mV vs. the normal hydrogen electrode (NHE) at pH 5.5, suggesting that a redox-mediated iron-release mechanism is a plausible hypothesis [7][8][9].…”