Transferrin-metal complexes

Strohmeier W (1968) Problem und Modell der homogenen Katalyse. 5 96-117 Sugiura Y, Nomoto K (1984) Phytosiderophores - Structures and Properties of Mugineic Acids and Their Metal Complexes. 58 107-135 Sun H, Cox MC, Li H, Sadler PJ (1997) Rationalisation of Binding to Transferrin Prediction of Metal-Protein Stability Constants. 88 71-102 Swann JC, see Bray RC (1972) II 107-144... 

The answer is b. (Hardman, pp 1324,1668. KatzmigT p 1009J Deferoxamine is the treatment of choice in acute Fe overload when the plasma concentration of Fe exceeds the total Fe binding capacity It has a high affinity for loosely bound Fe in Fe-carrying proteins such as ferritin, hemosiderin, and transferrin. The metal complex is excreted in the urine. 

Other metal complexes also have promising anticancer activity. Two Ti(IV) complexes are on clinical trial, an acetylacetonate derivative (budotitane) and titanocene dichloride, and the antimetastic activity of octahedral Ru(III) complexes is attracting attention, one of which is now on clinical trial. Ru(III), like several other metal ions, can be delivered to cells via the iron transport protein transferrin. 

V. Comparative Properties of the Metal-Free and Metal Complexes of Transferrins... 

With but few exceptions, definitive studies on the properties of the metal complexes have been done with human serum transferrin and chicken ovotransferrin, the majority having been done with the chicken ovotransferrin. Many of the properties of the metal complexes are very similar to, if not identical with, those of the metal-free proteins but also there are several rather distinctive differences. 

Table 9. Extinction coefficient of the transferrins and their metal complexes...

Studies of the optical rotatory dispersion of the transferrins and their metal complexes have not only shown important differences between the two forms of the proteins but also have afforded penetrating insight into the possible groups involved in chelation of the metal and in the structure of the complex (128, 129). These authors studied both chicken ovotransferrin and human serum transferrin and obtained essentially identical results with both proteins. Metal-free ovotransferrin had a plain negative rotatory dispersion between 300 and 675 mjj. with a specific rotation,... 

Like the studies with optical rotatory dispersion, studies with electron spin (paramagnetic) resonance not only have revealed important differences among the metal-free transferrins and their metal complexes but also have given insight into the nature of the binding sites and the structure of the complexes. Aasa et al. (1) reported on the iron and copper complexes of human serum transferrin and chicken ovotransferrin while Windie et al. 137) reported on human serum transferrin, human lacto-transferrin, chicken ovotransferrin, quail ovotransferrin, and turkey ovotransferrin. 

This relatively greater stability of the metal complexes of the transferrins was recognized early. Fiala and Burk (46), Fraenkel-Conrat (48) and Warner and Weber (132) reported that the iron complexes were more stable to treatment with formaldehyde, trypsin, and alkali, respectively,... 

Comparisons of the iron and copper complexes of the transferrins (128, 129) showed that the iron transferrin had a negative Cotton effect at the absorption maximum of the iron complex while the copper complex showed no such relationship. They concluded that the copper did not form an asymmetric center in the metal complexes, whereas the iron did form an asymmetric center. 

Feeney, R. E., and St. K. Komatsu Role of Tyrosines in Metal-Complexing Properties of Transferrins. (To be presented at the 152nd meeting of the American Chemical Society, September 12-18, 1966, New York, N. Y.) The role of hydroxyls (tyrosyls) in the binding of metals by human serum transferrin and chicken ovotransferrin has been shown by chemical means. Acetylation of the transferrins with N-acetyl imidazole inactivated the metal-binding activity. Deacetylation of the acetylated transferrins with hydroxylamine reactivated the transferrins. 

Atari, P. R. and R. E. Feeney Resistance of metal complexes of conalbumin and transferrin to proteolysis and to thermal denaturation. J. Biol. Chem. 232, 293 (1958). 

The metal complexation of ampholytes may cause unwanted results when iron-containing tools are used for handling the sample (e.g., syringes with metal needles, metal tubing, etc.). This was demonstrated with transferrin, a metalbinding protein, when iron-complexed forms of transferrin appeared in the mobilization pattern of an iron-free sample upon mixing the ampholytes and the protein solution with a Hamilton syringe equipped with metal needle [36]. 

Fig. 19. The visible absorption spectra of various metal complexes of human lactofer-rin all spectra are for 1% protein solutions. Very similar spectra are obtained for transferrin and ovotransferrin. Adapted from Ainscough et al. (135), with permission.

In vivo uptake of iron by transferrins usually involves its addition as a ferric-chelate complex, to prevent hydrolytic attack on the ferric ion (211). Complexes such as ferric citrate and ferric nitrilotriacetate are commonly used. Under these conditions, kinetic schemes for the uptake of iron by transferrins have identified five steps in the formation of the specific metal-anion-transferrin ternary complex (120). These may be summarized as follows. 

Labile proteins. These include proteins such as transferrin (which complexes iron, as discussed previously) and albumin (which complexes copper, zinc, and other metals). 

Spin echo measurements on metal complexes have been reviewed extensively by Mims and Peisach [267]. One use of this technique has been to study anion binding at paramagnetic metal centers. When cupric ion is substituted for ferric ion in transferrin, a pattern corresponding to the weak coupling for in C-doped bicarbonate indicates that bicarbonate is bound directly to the metal ion [269]. Thus, a modulation pattern detected by spin echo can confirm that adducts with a weakly coupled nuclear spin are bound directly to the metal site. 

CD studies of metal complexes (iron, copper) with human serum transferrin showed bands in the visible region (114) [earlier work in this field, mainly by ORD measurements is cited in Ref. (114)]. The binding of cupric or zinc ions to apotransferrin had no significant effect on the far ultraviolet CD (ORD) spectra (114). Similar results were also reported for chicken ovotransferrin (115). However, there were differences in the aromatic and other spectral regions up to 1000 nm between the CD spectra of the two copper transferrins indicating dissimilarities in the respective metal-binding sites (115). 

P.R. Azari and R.E. Feeney, Resistance of Metal Complexes of Conalhumin and Transferrin to Proteolysis and to Thermal Denaturation, J. biol. Chem. 232, 293-302 (1958). 

The importance of coordination in the biochemistry of essential metallic elements may be illustrated by numerous examples of metal complexes of which the following are representative the iron complex hemoglobin and numerous enzymes containing the heme and related structures such as catalases, peroxidases and cytochromes and the iron-containing proteins ferritin, transferrin, and hemosiderin the zinc complexes zinc-insulin, carbonic anhydrase and the carboxypeptidases the cobalt complex vitamin B12 the copper complex, ceruloplasmin the molybdenum-containing enzymes, xanthine oxidase, and nitrate reductase DNA-metal ion complexes. 

An additional mechanism for transport of metal complexes is by endo-cytosis/exocytosis (for review see Ballatori 1991). Fluid-phase, adsorptive, and receptor-mediated endocytosis make a major contribution to the transport of metals that are bound to high molecular weight ligands, and in particular to ligands such as ferritin, transferrin, and other proteins that are selectively cleared by receptor-mediated endocytosis. Because these proteins also have some affinity for toxic metals, they may play an important role in their transport across cell membranes (Ballatori 1991). The mechanism by which metallothionein and its associated metals are removed from the circulation is not known, but the kidney appears to be the principal site of removal (Tanaka et al. 1975). When rats are injected intravenously with ° Cd-labeled metallothionein, the radioactivity is rapidly and nearly completely accumulated in the kidney (Tanaka et al. 1975). 

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