Copper ceruloplasmin

Copper and Certdoplasmin in the Newborn and in Children. Tissue copper concentrations at birth are relatively high, particularly in the liver. However, concentration of copper in serum is lower at birth than at any other time. It is particularly high in the mother, approximately five times as much as that of the newborn (118). It is believed that the difference between the mother and the baby is attributable to the diminished capacity of the newborn to synthesize ceruloplasmin (16). Since unbound copper can pass the placental barrier, its concentration is the same on both sides of the placenta, but this is not the case with the protein-bound copper ceruloplasmin, which constitutes the majority of copper in serum. 

M12. Markowitz, H., Gubler, C. J., Mahoney, J. P., Cartwright, G. E., and Wintrobe, M. M., Studies on copper metabolism. XIV. Copper, ceruloplasmin and oxidase activity in sera of normal human subjects, pregnant women, and patients with infection, hepatolenticular degeneration and nephrotic S3mdrome. J. Clin. Invest. 34, 1498-1508 (1955). 

RIO. Rice, E. W., Correlation between serum copper ceruloplasmin activity and C-reac-tive protein. Clin. Chim. Acta 6, 632-636 (1960). 

Dameron, C.T. and Harris. E.D. (1987b) Regulation of aortic CuZn-superoxide dismutase with copper. Ceruloplasmin and albumin re-activate and transfer copper to the enzyme in culture. Biochem. J. 248 669-675. 

In general, serum copper values parallel those of ceruloplasmin. Therefore, serum copper is frequently low in patients with Wilson disease. However, about half of patients have serum copper levels in the normal range. Patients with fulminant Wilson disease and/or hemolytic anemia may even have markedly increased levels. Most of the copper in serum is bound to ceruloplasmin, and nnder normal conditions, less than 5% circulates as free copper and does not exceed 10 pg dl in normal subjects. The free copper concentration can be calculated by subtracting from the total copper concentration the ceruloplasmin bound copper (ceruloplasmin times 3.3). 

Copper is one of the twenty-seven elements known to be essential to humans (69—72) (see Mineral nutrients). The daily recommended requirement for humans is 2.5—5.0 mg (73). Copper is probably second only to iron as an oxidation catalyst and oxygen carrier in humans (74). It is present in many proteins, such as hemocyanin [9013-32-3] galactose oxidase [9028-79-9] ceruloplasmin [9031 -37-2] dopamine -hydroxylase, monoamine oxidase [9001-66-5] superoxide dismutase [9054-89-17, and phenolase (75,76). Copper aids in photosynthesis and other oxidative processes in plants. 

Ceruloplasmin Binds Copper, Low Levels of This Plasma Protein Are Associated With Wilson Disease... 

Ceruloplasmin (about 160 kDa) is an a2-globulin. It has a blue color because of its high copper content and... 

Copper is an essential trace element. It is required in the diet because it is the metal cofactor for a variety of enzymes (see Table 50—5). Copper accepts and donates electrons and is involved in reactions involving dismu-tation, hydroxylation, and oxygenation. However, excess copper can cause problems because it can oxidize proteins and hpids, bind to nucleic acids, and enhance the production of free radicals. It is thus important to have mechanisms that will maintain the amount of copper in the body within normal hmits. The body of the normal adult contains about 100 mg of copper, located mostly in bone, liver, kidney, and muscle. The daily intake of copper is about 2—A mg, with about 50% being absorbed in the stomach and upper small intestine and the remainder excreted in the feces. Copper is carried to the liver bound to albumin, taken up by liver cells, and part of it is excreted in the bile. Copper also leaves the liver attached to ceruloplasmin, which is synthesized in that organ. 

Ceruloplasmin contains substantial amounts of copper, but albumin appears to be more important with regard to its transport. Both Wilson disease and Menkes disease, which reflect abnormahties of copper metabohsm, have been found to be due to mutations in genes encoding copper-binding P-type ATPases. 

Lovstad, R.A. (1984). Catecholamine stimulation of copper-dependent haemolysis protective action of superoxide dismutase, catalase, hydroxyl radical scavengers and scrum proteins (ceruloplasmin, albumin and apotransferrin). Acta Pharmacol. Toxicol. 54, 340-345. 

Copper appears as the a2-globulin ceruloplasmin in the human body (Sarkar 1994). Deficiency of this protein in serum is characteristic of both Menkes and Wilson s diseases. Wilson s disease is an abnormal storage of Cu(II) in body tissues. Cu(II) in biological material can be determined by spectrophotometry or by FAAS, ceruloplasmin in serum by a spectrophotometric method. 

Ceruloplasmin is a protein for which many functions have been proposed - somewhat akin to Pirandello s Six Characters in Search of an Author, ceruloplasmin has long been a protein in search of a function. However, its importance in iron metabolism has been underlined by the observation of systemic iron loading in the tissues of patients with aceruloplasminaemia and other mutations in the ceruloplasmin gene. For further information on copper and iron interactions, see Chapter 12. 

Figure 12.4 Proposed path for the intracellular transfer of Cu(I) by Atxl. Copper destined for incorporation into the vascular multicopper oxidase Fet3 requires both Ctrl and Ccc2. Cytoplasmic Cu(I)-Atxl, but not apo-Atxl, associates with the amino-terminal domain of Ccc2 and Cu(I) is transferred to the latter. (Inset) A proposed mechanism for the exchange of Cu(I) involving two- and three-coordinate Cu-bridged intermediates. The human homologues of Atxl (Hahl), Ccc2 (Menkes and Wilson s proteins) and Fet3 (ceruloplasmin) are likely to employ similar mechanisms. Reprinted with permission from Pufahl et al., 1997. Copyright (1997) American Association for the Advancement of Science.

Catalytic reduction of oxygen directly to water, while not as yet possible with traditional catalyst technology at neutral pH, is achieved with some biocatalysts, particularly by enzymes with multi-copper active sites such as the laccases, ceruloplasmins, ascorbate oxidase and bilirubin oxidases. The first report on the use of a biocatalyst... 

The disease results from mutations within the ATP7B gene on the short arm of chromosome 13 [23, 24]. This gene encodes a protein which appears to be involved in copper transport coupled with the synthesis of ceruloplasmin and other cuproproteins. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

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