Transferrin complex

E S R.. Fenton. Transferrin Complexes with Non-Physiological and Toxic Metals, David M. Taylor. Transferrins, Edward N. Baker. Galactose Oxidase, Peter Knowles and Nobutoshi Ito. Chemistry of Aqua Ions of Biological Importance, David T. Richens. From a Structural Perspective Structure and Function of Manganese - Containing Biomolecules, David C. Weatherburn, Index. Volume 3,1996,304 pp. 109.50/ 70.00 ISBN 1-55938-642-8... 

Iron(III) citrate, " " or iron(III) ammonium citrate, is the usual vehicle for administering supplementary iron to an iron-deficient patient, for inducing iron-overload in rats or other creatures prior to testing the efficacy of iron chelators, or for introducing the isotope Fe for metabolic tracer studies. Stability constants for the aqueous iron(III)-citrate system have been established. " The 2 1 complex is claimed to be the dominant species in iron(III)/citrate/DMF systems. " There has been a very qualitative study of the incorporation of iron into transferrin from iron citrate. " Iron(III) citrate reacts relatively slowly with the aluminum(III)-transferrin complex to give the thermodynamically strongly favored combination of iron(III)-transferrin with aluminum(lll) citrate. " The mechanism of iron uptake from citrate complexes in cells has been briefly discussed. An octa-iron citrate complex appears in Section 5.4.5.4.3 below. 

The X-ray absorption spectra of a series of 28 model Fem complexes and those of ovatransferrin, protocatechuate 3,4-dioxygenase and catechol 1,2-dioxygenase have been analyzed, and appear to give information on the coordination number of the protein-bound iron. Thus the transferrin complexes appear to be six- or seven-coordinate, while the dioxygenase complexes could be five-or six-coordinate.816... 

Schade reviewed (114) the earlier studies on the role of serum transferrin in iron transport. Various early investigators had observed that the blood serum transferrin rapidly bound iron administered either through the gastrointestinal tract or by intravenous injection. There was a rapid turnover of iron in the blood serum and the degree of saturation of the transferrin was related to the amount of iron administered. In no instances, however, was the blood serum transferrin ever saturated with iron. Jandl et al. (71) have shown that both ovotransferrin and serum transferrin can transport plasma iron into red cells and that the transport is dependent on the concentration of transferrin. Iron taken up by the blood cells could not be eluted by subsequent incubation with iron-free transferrin solutions. More recently Morgan and Laurel (99) reported that iron uptake in reticulocytes is independent of the transferrin concentration. The iron complex of serum transferrin has a higher affinity for immature red cells than does the iron-free protein (72). Both bind specifically to immature red cells and the attachment permits the cells to remove the iron. Once the iron is removed, however, the iron-free transferrin can be replaced by an iron-transferrin complex. 

The physical scientist may be expected to develop a primary interest in the structure of the metal-transferrin complex. It is hoped that this structure may someday be seen by physical methods such as crystallography. 

Davis, B., P. Saltman, and S. Benson The stability constants of the iron-transferrin complex. Biochem. Biophys. Res. Commun. 8, 56 (1962). 

Al-transferrin complex is taken up by the parathyroid gland in a dose-dependent manner and... 

The dramatic role of the anion can perhaps best be appreciated from simple quantitative considerations. In the absence of a suitable anion, specific binding of iron to transferrin does not occur at all the effective binding constant is zero. At physiologic pH and bicarbonate concentrations, however, the effective binding constant is about 5 X 1023 M"1 24, 50). This means that in 1 L of blood plasma, in which the transferrin is only about 30% saturated with iron, there will be less than one free ferric ion or that a molecule of the ferric—transferrin complex will spontaneously dissociate only about once in 10,000 years. Since iron is readily removed from the transferrin molecule during its interaction with the reticulocyte without disrupting protein structure 51, 52), a... 

We believe these results are consistent with the hypothesis that the transferrin receptor of the rabbit reticulocyte is a protein with a complex subunit structure and a molecular weight near 350,000, so that the receptor-transferrin complex has an aggregate molecular weight of approximately 430,000, as measured by gel-filtration chromatography. A possible structure for the receptor itself, then, might consist of two subunits of molecular weight 95,000 and one of 165,000, for a total molecular weight of 355,000. 

Cannon, J. C., Chasteen, N. D. The Distinction between Metal Binding Sites in Vanadyl Transferrin Complexes in Proteins of Iron Storage and Transport in Biochemistry and Medicine, (ed.) Crichton, R. R, Amsterdam, North Holland Press, 1975... 

The chemistry of the group 13 metals makes binding studies difficult, as careful control of pH and bicarbonate concentration is necessary to prevent formation of species such as Al(OH)4 and Ga(OH)4". Nevertheless, UV difference spectra have shown that Al3+, Ga3 +, In3+, and Tl3 all form transferrin complexes with two metal ions per molecule (126, 144-146). Ae values imply the ionization of two tyrosines per bound metal ion, as for other specifically bound metals. NMR studies using 13C-enriched bicarbonate show virtually identical spectra for Al3+ and Ga3+, implying equivalent metal-anion environments (99). 

Al3+ (ionic radius, 0.54 A) is smaller than Fe3+ but still forms a stable transferrin complex, with binding constants 10125 and 10.13 5 Al3+ is displaced by Fe3+ (144) but the Al2Tf complex is stable enough that it has been shown to bind to cell surface receptors (164). Small-angle X-ray scattering experiments, however, indicate that the Al3+-transferrin complex is conformationally distinct from the diferric... 

Lanthanide complexes of transferrin have been used for several purposes. Gd3+-transferrin gives a characteristic EPR signal at g = 4.96, quite unlike the spectra for other Gd3+ complexes (165) Eu3+ has been used to probe differences between the two sites by Eu(III) excitation spectroscopy (168) and the luminescence of excited Tb3+ ions bound in one site of mixed-metal Tb3+-Mn3+ and Tb3+-Fe3+ transferrin complexes has been used to determine the intersite distance (169). The value obtained, 35.5 A, compares well with the value of 42 A later obtained from the lactoferrin crystal structure (67). 

The concept that transferrin complexes of larger metal ions may not exhibit the same closed structure as that of Fe3+ is not incompatible with spectroscopic studies. UV difference spectra reflect tyrosine coordination, and it is known that the open , metal-free structure has both tyrosines close together, adjacent to the (bi)carbonate site on domain 2 (80), but far (8 to 9 A) away from the remaining Asp and His ligands... 

Fig. 23. Visible absorption spectra for diferric transferrin complexes utilizing various synergistic anions, showing the variation in mal for the charge transfer band. Anions are 1, nitrilotriacetate 2, carbonate 3, salicylate 4, thioglycolate 5, glycine 6, glyoxy-late and 7, glycolate. From Schlabach and Bates (178), with permission.

Conformational change to the final specific transferrin complex. 

Transferrin is a reversible iron-binding protein used in vertebrate iron-transport see Iron Proteins for Storage Transport their Synthetic Analogs). Manganese will bind to transferrin in vitro to form a Mn -transferrin complex. Transferrin appears to bind the majority of the serum Mn and may be important in Mn transport. 

Ga(III) and In(III) (Group IIIB) have properties similar to Fe(III) except that their reduction potential to the +2 species is much lower and not attained under physiological conditions. Thus, the +3 oxidation state is exclusively observed in radiopharmaceutical chemistry. The formation of hydrolysis products and formation of transferrin complexes (Ga(III)-transferrin log Ki = 20.3 In(III)-transferrin log Ki = 18.74 ) must be considered in the design of radiopharmaceuticals based on Ga(III) and In(III) see Iron Proteins for Storage Transport their Synthetic Analogs). Therefore, the majority of Ga(III) and In(III) coordination complexes used as radiopharmaceuticals or as BFCA, to link Ga(III) and In(III) to antibodies or... 

Ga-citrate is also commonly used for imaging infection and inflammation. " At sites of inflammation, the gallium-transferrin complex leaks into the extracellular space and Ga is transchelated from transferrin in blood to lactoferrin and siderophores see Iron Transport Siderophores), which are released by leukocytes and bacteria. Imaging with Ga takes place usually 24-72h following injection. 

Cheng Y, Zak O, Aisen P, Harrison SC, Walz T. Structure of the human transferrin receptor-transferrin complex. Cell 2004 116 565-576. 

Transferrin is mainly synthesized in the hepatocytes. There are about 20 known variants. Iron is transported by transferrin (approx. 30% of transferrin is saturated with iron). With the help of a membrane receptor, the iron-transferrin complex is taken up and released in the liver cell, where it is immediately bound (because of its toxicity) to ferritin. The liver cells take up iron predominantly from transferrin, to a lesser degree also from haptoglobin, haemopexin, lactoferrin and circulating ferrin. Transferrin, which is mainly formed in the hepatocytes, may also bind and transport, in decreasing order, chromium, copper, manganese, cobalt, cadmium, zinc and nickel. The half-life of transferrin is 1 - 2 hours, which is very short in view of its total blood concentration of 3-4 mg. Approximately 0.4 g ferritin iron is stored in the liver. In the case of transferrin deficiency, its bacteriostatic and fungistatic effects are also reduced. Transferrin without iron saturation is known as apo-transferrin. (31, 66, 67)... 

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