Thermodynamic binding constants of the zinc-human serum transferrin complex

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Abstract
Serum transferrin is a mammalian Fe-transport protein. It has 2 specific metal-binding sites that bind a variety of metal ions in addition to ferric ion. Equilibrium constants for the binding of Zn(II) were determined by difference UV titrations using nitrilotriacetic acid and triethylenetetramine as competing ligands. The values are log K1* = 7.8 and log K2* = 6.4 in 0.10 M N-(2-hydroxyethyl)piperazine-N''-2-ethanesulfonic acid and 15 mM bicarbonate, pH 7.4 at 25.degree. C. Titrations of the 2 forms of monoferric transferrin show that K1* corresponds to Zn binding to the C-terminal site and K2* corresponds to binding at the N-terminal site. At serum bicarbonate concentrations, transferrin should have a higher affinity for Zn(II) than serum albumin and therefore could play some role in Zn transport. A linear free-energy relationship was constructed which relates the formation constants of a series of Zn(II) and Fe(II) complexes. On the basis of the Zn-transferrin binding constants, this relationship was used to estimate an Fe(II)-transferrin binding constant of 107.4. Using this ferrous constant and literature values for the ferric transferrin binding constant, one calculates a ferric transferrin reduction potential of -140 mV, which is easily within the range of physiological reductants. Such a result tends to support mechanisms for Fe removal from transferrin in which the ferric ion is reduced to the less tightly bound ferrous ion.