iron

• Living organisms need methods for transporting and storing trace metals; as free unbound metals (even Fe) are extremely toxic, storage must be in a non-toxic form.
• An iron based metabolic disease is described in optional external reading.
• Free iron acts as a catalyst for the formation of reactive oxygen species via the Fenton reaction: Fe2+ + H2O2 → Fe3+ + HO• + OH–.
• A 70 kg human needs 6 - 40 mg of Fe per day.
• Even though no Fe is actually lost through excretion there is potential loss from bleeding (internal & external).
• The amount of Fe stored in the body far exceeds that in use.
• The major storage reservoir for Fe is as ferritin which is widely distributed in the liver, spleen and bone marrow.
• Ferritin is a hollow protein with an Fe(III) hydroxide cluster core with a diameter of ~ 80 Å.
• The coating of ferritin has been shown by X-ray diffraction to consist of 24 subunits each of which is a polypeptide chain.
• Ferritin as a model for developing 3rd generation nano architecture organic/inorganic hybrid photo catalysts for energy conversion.
• Transferrin transports ca. 40 mg of iron/day to the bone marrow.
• The structure of transferrin is a single polypeptide coiled in such a way as to contain two pockets suitable for binding Fe3+.
• Each pocket of transferrin presents hard N- and O-donors to the metal centre but the presence of a carbonate CO3 2- or bicarbonate HCO3- ion is also essential.
• The affinity of transferrin for Fe3+ is extremely high (1023 M-1 at pH 7.4).
• At pH 7.4, the dissociation constant (K) of transferrin for Fe3+ is 1023 M-1 but as pH is lowered K drops until eventually log K transferrin < log K citrate.
• A plasma membrane oxidoreductase reduces transferrin bound iron from the Fe3+ state to Fe2+, directly or indirectly facilitating the removal of iron from the protein.
• Transferrin bound to two iron ions binds to a transferrin receptor on the cell surface.
• The protein enters the cell by receptor mediated endocytosis - and is then encapsulated within a vesicle within the cell.
• Proton pumps in the vesicle membrane pump H+ into the vesicle to reduce the pH to 5.5.
• Transferrin releases the iron - and the transferrin receptor complex is then transported to the cell surface.
• Aerobic micro-organisms cannot absorb iron from their aqueous environment since for Fe(OH)3 Ksp ~ 2.65 x 10-39.
• Aerobic micro-organisms use polydentate ligands called siderophores to scavenge iron.
• Each ligand supplies six O-donors for chelation in a potentially octahedral geometry.
• Examples of siderophores include enterobactin, desferrichrome and desferrioxamine B.
• The complexes of Fe3+ have very high stability, and it is likely that an Fe2+ intermediate is involved in release as stability constant is lower.
• Enterobactin, produced by E. coli H6L, contains 3 catechol groups and can deprotonate to bind Fe3+ as an octahedral complex [FeL]3-.
• Ionic radius of Fe3+ = 0.58 Å, V4+ = 0.65 Å.
• Cyclic peptide siderophores are produced by fungi and adopt the opposite configuration to enterobactin when complexed.
• Desferrioxamine B, produced by Streptomyces pilosus and Streptomyces coelicolor, is currently the most commonly prescribed drug for treating iron overload.
• Desferrioxamine-B has to be delivered through a needle under the skin for a period of nine to 12 hours several times a week due to its high cost, ineffectiveness when taken orally, and rapid degradation in the bloodstream.
• Deferiprone (Ferriprox) and deferasirox (Exjade) are orally-active drugs for treating iron overload that have reached the market.
• Deferiprone mimics the bidentate binding units found in siderophores.
• Deferiprone acts as a bidentate ligand, requiring three drug molecules to encapsulate the Fe3+ in the form of a 3:1 complex.
• The three bidentate ligands in deferiprone are not connected to a backbone, allowing them to dissociate more easily from the metal and open up coordination sites on the Fe3+ centre, leading to the generation of toxic hydroxyl radicals.
• Deferiprone was approved as an alternative treatment for patients who experience problems with desferrioxamine-B in Europe.
• Deferasirox contains a nitrogen donor in addition to two phenolic oxygen donors.
• Deferasirox acts as a tridentate ligand, occupying all six co-ordination sites of the Fe3+ centre.
• The resulting 2:1 complex of deferasirox has greater thermodynamic and kinetic stability than the Fe3+-deferiprone complex.
• The US Food and Drug Administration (FDA) approved deferasirox worldwide for treating chronic iron overload in 2005.
• Free iron is toxic and can trigger the Fenton reaction, leading to the production of reactive oxygen species (ROS).