Iron mobilization from transferrin by therapeutic iron chelating agents

The bacteriostatic activity of the transferrin family has been known since the early 1960's. The possession of high affinity iron(III)-binding sites and the existence of a specific membrane-bound receptor, have led to the present understanding of serum transferrin acting as the major iron transporter between cells in vertebrate systems. Iron chelators can interact with transferrin, either by directly donating iron or by removing iron from the protein; both interactions have relevance for haematology.

Urea polyacrylamide gels and HPLC methods have been developed for the resolution and quantification of the four major forms of transferrin, diferric-transferrin, C-mono Fe-transferrin, N-mono Fe-transferrin and apo transferrin.

Negatively charged ligands with pFe values >20 remove iron from transferrin, preferably from the N-lobe iron-binding site. Some siderophores are capable of removing iron from transferrin. 3-Hydroxypyridin-4-ones, lacking a negative charge are able to remove iron from transferrin with a strong preference for the C- lobe iron-binding site. The donation of iron to apo transferrin by hydroxypyridinone iron(III) complexes has relevance to the treatment of clinical anaemias, because the hydroxypyridinones can also mobilize iron from the reticuloendothelial system and so facilitate the redistribution of iron from macrophages to reticulocytes.

Hydroxypyridinones have excellent potential for facilitating the redistribution of iron and this has relevance to the treatment of many disease types, including neurodegeneration and clinical anaemias. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.