Transferrin binding Al³⁺ and Fe³⁺

An understanding of Al³⁺-induced diseases requires identification of the blood carrier of Al³⁺ to the tissues where Al³⁺ exerts a toxic action. Quantitative studies demonstrate that the protein transferrin (iron-free) is the strongest Al³⁺ binder in blood plasma. Under plasma conditions of pH 7.4 and [HCO₃-]27 mmol/L, the successive constant values for Al³⁺ binding to transferrin are log K₁ = 12.9 and log K₂ = 12.3. When the concentration of total Al³⁺ in plasma is 1 μmol/L, the free Al³⁺ concentration permitted by transferrin is 10^-14.6 mol/L, less than that allowed by insoluble Al(OH)₃, by Al(OH)₂H₂PO₄, or by complexing with citrate. Thus transferrin is the ultimate carrier of Al³⁺ in the blood. We also used intensity changes produced by metal ion binding to determine the stability constants for Fe³⁺ binding to transferrin: log K₁ = 22.7 and log K₂ = 22.1. These constants agree closely with a revision of the reported values obtained by equilibrium dialysis. By comparison with Fe³⁺ binding, the Al³⁺ stability constants are weaker than expected; this suggests that the significantly smaller Al³⁺ ions cannot coordinate to all the transferrin donor atoms available to Fe³⁺.