The Fe(III)- and anion-binding functions of transferrin are strongly interdependent, with specific binding of either dependent on the presence of the other. Under physiologic conditions, bicarbonate is the anion preferentially bound by transferrin, although a variety of other anions are also capable of occupying the specific anion-binding site of the protein. Because of its possible role in the uptake of iron from transferrin by the reticulocyte, studies were undertaken of the exchangeability of transferrin-bound bicarbonate with bicarbonate free in solution. The rate of exchange depends on the anionic composition of the medium. At physiological pH and ambient p-CO2, bicarbonate exchange is detectable but slow, with a half-time of about 20 days. The presence of millimolar concentrations of citrate or nitrilotriacetate increases the exchange rate by two orders of magnitude. Increasing the bicarbonate concentration also increases the exchange rate in an approximately proportional manner. The exchange of bicarbonate from monoferric transferrin prepared by isoelectric focusing is describable by a simple first-order plot. However, exchange from diferric transferrin is more complex and requires two exponential terms to fit the data satisfactorily. In every case studied the half-time for exchange in mono-ferric transferrin has a value intermediate to the two half-times for exchange in differric transferrin. These results point to an interaction between the two specific anion-binding sites of the protein. They may account, in part, for the observed difference in the rates at which iron is taken up from the two iron-binding sites of transferrin by the reticulocyte.
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