Transferrin ceruloplasmin and

Although both GPx and Cat are very efficient in removing H202, HO can still be formed in abundance (Fenton and Haber-Weiss chemistry). To partially offset the influence of transition metal ions on free radical production, there are numerous metal-binding proteins which prevent these reactions from taking place these include, among others, ferritin, transferrin, ceruloplasmin, and metallotheinein (Table 2). 

Table 50-2 summarizes the functions of many of the plasma proteins. The remainder of the material in this chapter presents basic information regarding selected plasma proteins albumin, haptoglobin, transferrin, ceruloplasmin, aj-antitrypsin, aj i roglobulin, the immunoglobulins, and the complement system. The lipoproteins are discussed in Chapter 25. 

Fig. 3. Pattern of heterophile antibodies (HA reciprocal units of dilution), immunoglobulins (IgA, IgG, and IgM), transferrin (Tf), and ceruloplasmin (Cp) throughout gestation in malaria-protected pregnant women. The numbers of investigations at each period of gestation are indicated in parentheses at the bottom of the graph where this differs, as in the case of ceruloplasmin, the numbers are so indicated. Note the increase of serum IgM and transferrin until just before term, when there is also a decrease of the IgG. Ceruloplasmin and heterophile antibodies show a decrease in mean concentration from 25 to 28 weeks of gestation.

Transferrins bind Fe2+ weakly and it is likely that a transferrin- Fe2+-HC03- complex formed initially undergoes oxidation to the Fe3+-C032- complex within cells and within the bloodstream. A conformational change closes the protein around the iron ions.56 In yeast the previously mentioned copper oxidoreductase encoded by the FET3 gene appears to not only oxidize Fe2+ but also transfer the resulting Fe3+ to transferrin. Ceruloplasmin may play a similar role in mammals.33... 

Hypoproteinemia may result in low levels of serum calcium, ceruloplasmin, and transferrin. Because losses of iron are at most 0.5-1.0 mg/24 hr, even with the heaviest proteinuria, other factors must operate to produce iron deficiency and microcytic hypochromic anemia. Although the copper-binding protein ceruloplasmin is lost in the urine in nephrotic subjects and its plasma levels are low, plasma and red cell copper concentrations are usually normal. Zinc circulates mainly bound to albumin and also to transferrin, and thus the reported reduction zinc concentration in plasma, hair, and white cells in nephrotic patients is not surprising. 

An absence of R-type binding protein has been reported in two adult siblings by Carmel and Herbert (C20). R-Type protein was virtually absent from their leukocytes and saliva, and as was expected they had very low levels of serum vitamin B12. The absence of the protein did not appear to have any adverse effects. Other members of this family have also been found to have an absence of, or very low levels of, R-protein (H26). There was no general deficiency of plasma glycoproteins in these patients and the amounts of thyroid binding globulin, thyroxine, ceruloplasmin, and transferrin were all normal. 

A second member of the ceruloplasmin family multicopper oxidases with six BCB domains was recently identified as the causative agent of sex-linked anemia (sla) in mice (Vulpe et al., 1993). It was named hephaes-tin and shown to be expressed mostly in the small intestine and the colon, where it is presumably involved in gastrointestinal iron uptake. Hephaes-tin displays a high level of sequence identity to ceruloplasmin and differs from it only by an additional C-terminal transmembrane domain, which anchors the protein to the cell membrane. A 582-nucleotide in-frame deletion in the mRNA for hephaestin sla mice has been identified compared to normal animals. The mice with such a mutation are unable to release iron from enterocytes (intestinal epithelial cells) into the circulation, which results in severe anemia. The GPI-anchored form of ceruloplasmin could potentially also mediate similar cellular iron efflux in the central nervous system. There is a transferrin-independent iron uptake system that requires Fe(III) to be reduced to Fe(II) at the cell surface for uptake to occur (DeSilva et al., 1996). Ceruloplasmin would oxidize Fe and prevent its uptake by this mechanism. Briefly, the role of ceruloplasmin is most likely to prevent excessive intracellular iron accumulation by tightly controlling iron efflux and inhibiting its uptake. 

The specific interaction of Cibacron Blue and its derivatives to dinucleotides, mainly to NAD, NADP and ATP offers the possibility of purifing all enzymes which are dependent on these coenzymes. According to Mosbach < - > there are 163 enzymes requiring NAD, 141 enzymes requiring NADP, about 40 enzymes requiring NADP or NAD and 225 enzymes dependent on ATP. Besides these specific interactions non-specific interactions of Cibacron Blue and its derivatives with. proteins can also be applied for separation purposes. The non-specific interaction of Cibacron Blue with human serum albumin, for instance, enables albumin to be removed from transferrin, ceruloplasmin or other plasma proteins in order to purify human... 

There is some evidence that ceruloplasmin is involved in iron metabolism. It has been suggested that ceruloplasmin and ferritin in plasma work together to reduce the levels of free ferrous ions in plasma. Here, the ceruloplasmin catalyzes the oxidation of Fe (ferrous) to (ferric), the form of the metal that binds to ferritin. Ceruloplasmin acts as an oxidant in this process. This proposed function may reduce damage to membrane lipids possibly inflicted by the small amount of Fe in the circulation. It is thought that ceruloplasmin may be used in the mobilization of iron from intracellular stores. Here, the protein may facilitate the transfer of iron from ferritin to transferrin [Frieden and Hsieh, 1976), A relationship between copper and irtm is suggested by the fact that copper-deficient rats may develop iron deficiency anemia, as revealed by measurements of hemoglobin and hematocrit (Johnson and Dufault, 19S9 Cohen et a ., 1985), Ceruloplasmin may also function in a unique iron transport mechanism, as mentioned in the Iron section. 

Most aspects of intermediary metabolism require essential trace elements in the form of metalloenzymes that have a range of catalytic properties. Specific metalloproteins are required for the transport and safe storage of very reactive metal ions, such as Fe or Cu. Examples are metaUo-thionein (Cu, Zn), transferrin, ferritin and hemosiderin (Fe), and ceruloplasmin (Cu). 

Iron Metabolism. Copper-containing enzymes— namely ferroxidase I (ceruloplasmin) and ferroxidase II, and the recently described hephaestin in the enterocyte—oxidize ferrous iron to ferric iron. This allows incorporation of Fe into transferrin and eventually into hemoglobin. Ferroxidase II is a yellow protein, the importance of which in iron metabolism is not as well characterized as that of ceruloplasmin. 

Transferrin synthesised by the oligodendrites in the brain will bind the majority of the iron that traverses the blood—brain barrier after the oxidation of the iron, possibly by a glycophosphoinositide-linked ceruloplasmin found in astrocytic foot processes that surround brain endothelial cells. Neurons acquire iron from diferric transferrin. However, the source of iron within microglia cells is unclear — other phagocytic cells such as macrophages, take up iron via transferrin receptors and release iron via ferroportin. 

Binding those metal ions in a metalloprotein usually prevents them from entering into these types of reactions. For example, transferrin, the iron-transport enzyme in serum, is normally only 30 percent saturated with iron. Under conditions of increasing iron overload, the empty iron-binding sites on transferrin are observed to fill, and symptoms of iron poisoning are not observed in vivo until after transferrin has been totally saturated with iron. Ceruloplasmin and metallothionein may play a similar role in preventing copper toxicity. It is very likely that both iron and copper toxicity are largely due to catalysis of oxidation reactions by those metal ions. 

FET3 gene product of S. cerevisiae is a multicopper oxidase and plays a key role in iron metabolism of this eukaryote has underpinned the function of ceruloplasmin in vertebrate iron transport. By virtue of its ferroxidase activity, ceruloplasmin converts Fe(II) into Fe(III), which binds to the iron-binding protein transferrin. Ceruloplasmin is critical for iron egress from some cell types. The transport system responsible for iron release into plasma has not been identified. ... 

Hulsewe et al. 1997). Several of the plasma proteins that alter in hepatotoxicity include hhrinogen, haptoglobin, transferrin, ceruloplasmin, alphaj-macroglobulin, coagulation cascade and complement proteins, secretory IgA, carbohydrate deficient transferrin (CDT), and protein F (see Chapter 8). 

Transcriptional control of iron metabolism has been described, and therefore IRP is imlikely to be the only iron biosensor in mammals. The serum protein ceruloplasmin is transcriptionally regulated by iron in the human hepatocellular carcinoma line HepG2 [48]. Ceruloplasmin is a ferrous iron oxidase (ferroxidase) involved in both transferrin-dependent and -independent iron transport, but appears to facilitate only the latter in the carcinoma cell line. The factor(s) that mediate(s) transcriptional control of ceruloplasmin by iron is not yet known. 

The function of ceruloplasmin in the mammalian organism is presently unknown although there have been suggestions that it is required for the efficient incorporation of iron into transferrin (103), and that it is an essential component of copper mobilization (104—106). These have been the subject of considerable debate (107, 108 and references therein), and will not be of further concern here. 

Ceruloplasmin and Iron Transferrin in Human Malignant Disease Margaret A. Foster, Trevor Pocklington, and Audrey A. Dawson... 

Chromoproteins proteins which contain a colored prosthetic group bound covalently or noncova-lently. The group includes heme proteins and iron prophyrin enzymes, flavoproteins, chlorophyll-protein complexes, and the non-porphyrin iron and copper proteins in the blood of vertebrates (e. g. transferrin and ceruloplasmin), and invertebrates (e.g. hemery-thrin and hemocyanin). 

Once absorbed, metal ions and compounds enter the blood, mostly bound to blood cells and/or plasma proteins, which can be very specific (transferrins, ceruloplasmin). By the bloodstream metals are usually distributed throughout the body. Metallothioneins play an important role in distribution, function, detoxification, and maybe also toxicity of heavy metals [8]. There is a blood-brain barrier which can only be crossed by lipid-soluble molecules. Liver and kidney have a high capacity to bind metals. Bones and other mineralized tissues such as teeth can serve as storage organs for metals such as Ba, Be, Tl, Pb, Sr, La, Y. A number of metals have been shown to cross the placenta and to enter the fetal blood circulation. Biotransformation includes changes in the oxidation state, methylation processes, and cleavage of metal-carbon bonds. Gastrointestinal... 

Lactoferrin is an iron transport non-heme glycoprotein present in human milk and many biological secretions that can effectively inhibit the oxidation of various lipid systems by its iron-binding capacity. However, this protein can also have prooxidant activity, depending on the lipid system, and its concentration relative to the concentration of metal ions. Lactoferrin effectively inhibited oxidation and increased the oxidative stability of infant formulas supplemented with iron (see Chapter ll.C). Other known proteins that chelate or inactivate transition metals are found in biological systems including transferrin, albumin, and ceruloplasmin (Chapter 13). 

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