Ceruloplasmin ferroxidase activity

Ceruloplasmin Ferroxidase activity Cp-/- mice (Harris et al, 1999) Aceruloplasminaemia (Logan et al, 1994 Takahashi et al, 1996) deficient iron mobilization low serum iron tissue iron overload... 

In summary, normal hemoglobin production depends on the ferroxidase activity of ceruloplasmin. Since the ferroxidase activity of ceruloplasmin is dependent on the presence of copper in the molecule, a deficiency of copper results in a marked decrease in ceruloplasmin ferroxidase activity, which leads to anemia. 

Another condition involving ceruloplasmin is aceru-loplasminemia. in this genetic disorder, levels of ceruloplasmin are very low and consequently its ferroxidase activity is markedly deficient. This leads to failure of release of iron from cells, and iron accumulates in certain brain cells, hepatocytes, and pancreatic islet cells. Affected individuals show severe neurologic signs and have diabetes mellitus. Use of a chelating agent or administration of plasma or ceruloplasmin concentrate may be beneficial. 

The multi-copper oxidases include laccase, ceruloplasmin, and ascorbate oxidase. Laccase can be found in tree sap and in fungi ascorbate oxidase, in cucumber and related plants and ceruloplasmin, in vertebrate blood serum. Laccases catalyze oxidation of phenolic compounds to radicals with a concomitant 4e reduction of O2 to water, and it is thought that this process may be important in the breakdown of lignin. Ceruloplasmin, whose real biological function is either quite varied or unknown, also catalyzes oxidation of a variety of substrates, again via a 4e reduction of O2 to water. Ferroxidase activity has been demonstrated for it, as has SOD activity. Ascorbate oxidase catalyzes the oxidation of ascorbate, again via a 4e reduction of O2 to water. Excellent reviews of these three systems can be found in Volume 111 of Copper Proteins and Copper Enzymes (Lontie, 1984). 

Cartwright and Wintrobe and their co-workers suggested a link between copper deficiency and anemia in mammals 50 years ago (see Lahey et al., 1952). Cartwright subsequently demonstrated that this copper-dependent anemia was unresponsive to iron supplementation but was corrected on administration of ceruloplasmin (see Lee et al., 1968). The molecular basis of this link was indicated by Osaki and Friedan, who characterized the ferroxidase activity of ceruloplasmin and kinetically demonstrated that Cp could play a critical role in catalyzing trafficking of the potentially cytotoxic Fe(II) in the plasma to apoA f (see Frieden and... 

Lindley, P. E, Card, G., Zaitseva, I., Zaitsev, V., Reinhammar, B., Selin-Lindgren, E., and Yoshida, K. (1997). An X-ray structural study of human ceruloplasmin in relation to ferroxidase activity./. Biol. Inorg. Chem. 2, 454 63. 

Ceruloplasmin is a multifunctional enzyme capable of oxidizing phenols and aromatic amines (Musci et al., 1999). It can also efficiently oxidize Fe(II) to Fe(III), which is currently considered its main in vivo biological function. The ferroxidase activity of this enzyme was hrst reported in 1960 (Curzon and O Reilly, 1960) and it was later suggested that such activity is important for loading iron into the transferrin, since it binds only Fe(III) (Osaki, 1966). Recent studies on ceruloplasmin knockout mice demonstrated that they indeed exhibit a severe impairment of... 

In the yeast Sa. cerevisiae the functional homologue of ceruloplasmin is Fet3. It is a multicopper oxidase that displays ferroxidase activity similar... 

Iron entering the bloodstream from the gastrointestinal tract is thought to be present as Fe , and must be oxidized to Fe before binding to transferrin, which then delivers iron to many different types of cell. The non-enzymic route for oxidation of Fe in serum appears to be too slow for the formation of iron(III) transferrin. As noted in Section 62.1.8.5.1, the copper protein ceruloplasmin has ferroxidase activity, being responsible for the oxidation of Fe" to Fe . It is well known that deficiency of copper influences iron metabolism in animals, in accord with this role for ceruloplasmin. 

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. ... 

The evidence that ceruloplasmin (Cp) (E.C. 1.12.3,1) is a direct molecular link between copper and iron metabolism is summarized. Copper deficiency results in low plasma Cp and iron, reduced iron mobilization, and eventually anemia, even with high iron storage in the liver. Cp controls the rate of iron uptake by transferrin. Transferrin plays a key role in the availability of iron for the biosynthesis of hemo-globin in the reticulocytes. The ferroxidase activity of Cp results in the reduction of free iron ion generating a conr centration gradient from the iron stores to the capillary system, thus promoting a rapid iron efflux in the reticuloendothelial system. It has been confirmed both in vivo and in the perfused liver that lOr M Cp specifically induces a rapid rise in plasma iron. 

In conclusion, we befieve there is now ample evidence that the copper protein of serum, ceruloplasmin, is a molecular link between copper and iron metabohsm. It has been shown both in vitro and in vivo to be directly involved in iron mobilization, the rate of formation of Fe(III) transferrin, and perhaps ultimately of hemoglobin biosynthesis. While the precise mechanism of this effect is still under investigation, we believe that it is directly related to the ferroxidase activity of this serum enzyme. 

The inhibitory eflFects of trivalent and other metal ions on ferroxidase (ceruloplasmin) activity were investigated by Huber and Frieden (6J) and the results are summarized in Tables VI and VII. All trivalent cations tested inhibited ferroxidase activity but the strong trivalent inhibitors had an ionic radius of 0.81 A or less. The inhibition by Al(III) was mixed competitive and uncompetitive with respect to the substrate, Fe(II). The uncompetitive portion of the inhibition was not the result of competition by Al(III) with the other substrate, oxygen. A mechanism for the mixed inhibition by Al(III) was proposed consistent with these... 

Ceruloplasmin, 656,672,699, 700 cytochrome oxidases, 683 ferroxidase activity, 671 labelled... 

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