Role of Zinc ( II ) Ion for the Formation of Iron Deposition in Human Body and Its Significance

Iron depositions, one of the non-transferrin-bound iron (NTBI), are frequently observed for the patients with thalassemia, hemochromatosis and other iron-overloading disorders. In this article, we have pointed out that zinc(II) ion and hydrogen peroxide play a critical role in the formation of the iron deposition, and that the formation of iron deposition by zinc(II) ion should be one of the important method to protect the oxidative stress by water-soluble NTBI. This implies that the zinc(II) ions contribute to depress the oxidative stress by NTBI.

Plasma iron is normally bound to the iron transport protein transferrin.When excess chelates (amino acids derivatives, small peptides or citrate, etc.) are present in the plasma, the water-insoluble hemosiderin which contains polymeric iron(III) ions with oxo-bridges may dissolve with forming the water-soluble iron(III) chelates with amino-acids or citrates.These iron ions not associated with transferrin is generally termed as non-transferrin-bound iron (NTBI).NTBI is detected in the plasma of patients with thalassemia, hemochromatosis and other iron-overloading disorders, and is present at concentration up to 10 M (Dresow, Peterson, Fischer, & Nielsen, 2008;Fernaeus & Land, 2005;Gaeta & Hider, 2005).It should be noted here that NTBI has been thought to play an important role in iron induced cell damage with resultant peroxidation of cell membrane lipids and other biomolecules, and such oxidative damage is implicated as an important contributor in the pathogenesis of cancer, cardiovascular disease, aging and neurodegenerative diseases.
Despite numerous studies over the last 30 years since plasma NTBI was first postulated to exist, it is still poorly characterized.The inability thus far to characterize NTBI most likely reflects both its heterogeneous nature and the likelihood that the different forms will exist and vary with the concentration of the chelates such as amino-acids, peptides, and citrate, etc.At present, one of the most definitely definable NTBI should be iron deposition, which is frequently observed for patients of hemochromatosis and other iron-overloading disorders, and aceruplasminemia (Yoshida et al., 2000).The structure and role of the iron deposition is not known at present, which at present is only considered to be a signal to tell that the human body is iron-overlord state.In this article, we will demonstrate the several chemical models for NTBI and for the iron deposition, and propose the important role of zinc(II) ions to give iron deposition.

Formation and Structural Properties of Iron Deposition
As demonstrated above, the structure of the iron deposition is not clear at present.Here, I would like to propose that structure of the iron deposition should be similar to those of the models for hemosiderin, the structure of one of the hemosiderin models being illustrated in Figure 1 (Hearth & Powell, 1992).
Above compound is the water-insoluble iron(III) complex with H 3 (hida) (for the structure of this chelate, see Figure 2), and it should be noted here that 1) central seven iron(III) ions are surrounded by ten oxo anions (O 2 2-), 2) six oxo anions among the ten are coordinated to three iron atoms, and 3) the central part of this compound is the aggregation of eight di--oxo-diiron(III) species.These are implying that the oxo anions play an important role for the formation of the model of hemosiderin, and also for the formation of iron deposition.When excess H 3 (hida) was added to the solution containing above water-insoluble compound, the solid dissolved to form a clear solution, and from the solution the following compound, [Fe 2 (hida) 2 (H 2 O 2 ) 2 ] was obtained (Hearth & Powell, 1992), the structure of this complex being illustrated in Figure 3. Figure 3 clearly indicates that the exclusion of the oxo anions around the iron(III) ion leads to the formation of water-soluble species, which again supports that oxo anions are closely related with the formation of iron deposition.Similar facts are also observed for the case of H 2 (ida) chelate (see Figure 2).These facts are demonstrating that there is an equilibrium between the water-insoluble and water-soluble iron(III) species in the solution (see Scheme I), which is controlled by the concentrations of oxo-anion and chelates.Both the water-insoluble and water-soluble species are called as NTBI, but NTBI that play an important role in iron induced oxidative stress should be water-soluble ones (Nishida, 2009).
Scheme I

Zinc(II) Species Act as OH --Transporter to Give Iron Deposition
We have found that deposition of the iron(III) hydroxide occurs readily on the aggregates of amyloid beta-peptide (A (1-40)) when zinc(II) chloride solution is added to the solution (pH=7.4) containing iron(III) compounds with (nta), (edda), and other amino acid derivatives, and A(1-40) (Okawamukai, Sutoh, & Nishida, 2006).We have observed that the similar iron deposition has occurred on several proteins such as albumin or transferrin, indicating that iron deposition by zinc(II) ions are not specific for the amyloid proteins.
It seems quite likely that the formation of iron deposition observed above proceeds according to the Scheme III: zinc(II) complex which contains hydroxide ion (OH -) (Nishino et al., 2006) approaches to the protein, where the iron(III) complexes bind with the protein through two-point interaction (Scheme III) (Nishida, Itoh, & Satoh, 2007), and then the transfer of the hydroxide ion from the zinc(II) to the iron(III) ion occurs, to lead to the formation of di--oxo-iron(III) species, and finally to iron deposition as illustrated in Scheme II.In this reaction the zinc(II) ions are operating as OH --transporter to give di--oxo-iron(III) species on the protein.Since the total zinc(II) concentration is relatively reduced compared with that of normal cases, and massive iron deposition are observed in the brain and on several organs such as kidney or spleen of the aceruplasminemia patients (Yoshida et al., 2000), it seems reasonable to assume that zinc(II) ions play an important role on the formation of the iron deposition in the aceruplasminemia patients.Since the formation of the iron deposition means the deletion of toxic NTBI from the plasma, we can consider that zinc(II) ions act as an antioxidant in the patients of several neurodegenerative disorders.Thus, the amyloid deposition which frequently observed for the Alzheimer's patients, may be due to one of the antioxidative function by zinc(II) ion, which is consistent with the fact that amyloid deposits generally contain much quantities of iron(III) and zinc(II) ions (Bush, 2003).

Transferrin Rigorously Distinguishes and Recognizes the Structure of the Iorn(III) Chelates
Transferrins are group of iron-binding proteins, that include serum transferrin, lactoferrin and ovotransferrin; they are all glycoproteins that have a molecular mass of about 80 kDa, and bind two Fe 3+ per molecule with high affinity.Serum transferrin has a specific role as an iron transporter, delivering the bound iron to target cells via receptor-mediated endocytosis.But, the detailed mechanism of up-take of iron-ion from the solution by apo-transferrin remains unclear at present.

Figure 1 .
Figure 1.Structure of model compound of hemosiderin with H 3 (hida).In the center circle (Fe, black: oxygen, red), seven iron(III) ions are surrounded by ten oxo anions forming the aggregation of eight di--oxo-diiron(III) species Figure 4. Str