Ferric pyrophosphate citrate: interactions with transferrin.

There are several options available for intravenous application of iron supplements, but they all have a similar structure:—an ironcore surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrinand distributed throughout the body, with most of the ironsupplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity. A new parenteral ironformation, ferric pyrophosphatecitrate (FPC), has a novel structure that differs from conventional intravenous ironformulations, consisting of an ironatom complexed to one pyrophosphateand two citrate anions. In this study, we show that FPC can directly transfer ironto apo- transferrin. Kinetic analyses reveal that FPC donates ironto apo- transferrinwith fast binding kinetics. In addition, the crystal structure of transferrinbound to FPC shows that FPC can donate ironto both iron-binding sites found within the transferrinstructure. Examination of the iron-binding sites demonstrates that the ironatoms in both sites are fully encapsulated, forming bonds with amino acid side chains in the protein as well as pyrophosphateand carbonate anions. Taken together, these data demonstrate that, unlike intravenous ironformulations, FPC can directly and rapidly donate ironto transferrinin a manner that does not expose cells and tissues to the damaging effects of free, redox-active iron.