Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948.[4] Another protein, hephaestin, is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.
Ceruloplasmin is an enzyme (EC1.16.3.1) synthesized in the liver containing 6 atoms of copper in its structure.[5] Ceruloplasmin carries more than 95% of the total copper in healthy human plasma.[6] The rest is accounted for by macroglobulins. Ceruloplasmin exhibits a copper-dependent oxidase activity, which is associated with possible oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric iron), therefore assisting in its transport in the plasma in association with transferrin, which can carry iron only in the ferric state.[7] The molecular weight of human ceruloplasmin is reported to be 151kDa.
Regulation
A cis-regulatory element called the GAIT element is involved in the selective translational silencing of the Ceruloplasmin transcript.[8]
The silencing requires binding of a cytosolic inhibitor complex called IFN-gamma-activated inhibitor of translation (GAIT) to the GAIT element.[9]
Clinical significance
Like any other plasma protein, levels drop in patients with hepatic disease due to reduced synthesizing capabilities.
Copper availability doesn't affect the translation of the nascent protein. However, the apoenzyme without copper is unstable. Apoceruloplasmin is largely degraded intracellularly in the hepatocyte and the small amount that is released has a short circulation half life of 5 hours as compared to the 5.5 days for the holo-ceruloplasmin.
Mutations in the ceruloplasmin gene (CP), which are very rare, can lead to the genetic disease aceruloplasminemia, characterized by hyperferritinemia with iron overload. In the brain, this iron overload may lead to characteristic neurologic signs and symptoms, such as cerebellar ataxia, progressive dementia, and extrapyramidal signs. Excess iron may also deposit in the liver, pancreas, and retina, leading to cirrhosis, endocrine abnormalities, and loss of vision, respectively.
Deficiency
Lower-than-normal ceruloplasmin levels may indicate the following:
Wilson disease (a rare (UK incidence 2/100,000) copper storage disease).[10]
↑Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somatic Cell and Molecular Genetics. 13 (3): 285–92. doi:10.1007/BF01535211. PMID3474786.
↑Holmberg CG, Laurell CB (1948). "Investigations in serum copper. II. Isolation of the Copper containing protein, and a description of its properties". Acta Chem Scand. 2: 550–56. doi:10.3891/acta.chem.scand.02-0550.
↑Ziakas A, Gavrilidis S, Souliou E, Giannoglou G, Stiliadis I, Karvounis H, Efthimiadis G, Mochlas S, Vayona MA, Hatzitolios A, Savopoulos C, Pidonia I, Parharidis G (2009). "Ceruloplasmin is a better predictor of the long-term prognosis compared with fibrinogen, CRP, and IL-6 in patients with severe unstable angina". Angiology. 60 (1): 50–9. doi:10.1177/0003319708314249. PMID18388036.
Mazumder B, Seshadri V, Fox PL (Feb 2003). "Translational control by the 3'-UTR: the ends specify the means". Trends in Biochemical Sciences. 28 (2): 91–8. doi:10.1016/S0968-0004(03)00002-1. PMID12575997.
Giurgea N, Constantinescu MI, Stanciu R, Suciu S, Muresan A (Feb 2005). "Ceruloplasmin - acute-phase reactant or endogenous antioxidant? The case of cardiovascular disease". Medical Science Monitor. 11 (2): RA48–51. PMID15668644.
Polosatov MV, Klimov PK, Masevich CG, Samartsev MA, Wünsch E (Apr 1979). "Interaction of synthetic human big gastrin with blood proteins of man and animals". Acta Hepato-Gastroenterologica. 26 (2): 154–9. PMID463490.
Walker FJ, Fay PJ (Feb 1990). "Characterization of an interaction between protein C and ceruloplasmin". The Journal of Biological Chemistry. 265 (4): 1834–6. PMID2105310.
Fleming RE, Gitlin JD (May 1990). "Primary structure of rat ceruloplasmin and analysis of tissue-specific gene expression during development". The Journal of Biological Chemistry. 265 (13): 7701–7. PMID2332446.
Yang FM, Friedrichs WE, Cupples RL, Bonifacio MJ, Sanford JA, Horton WA, Bowman BH (Jun 1990). "Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing". The Journal of Biological Chemistry. 265 (18): 10780–5. PMID2355023.
Mercer JF, Grimes A (Jul 1986). "Isolation of a human ceruloplasmin cDNA clone that includes the N-terminal leader sequence". FEBS Letters. 203 (2): 185–90. doi:10.1016/0014-5793(86)80739-6. PMID3755405.
Rask L, Valtersson C, Anundi H, Kvist S, Eriksson U, Dallner G, Peterson PA (Jan 1983). "Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens". Experimental Cell Research. 143 (1): 91–102. doi:10.1016/0014-4827(83)90112-X. PMID6337857.
Kressner MS, Stockert RJ, Morell AG, Sternlieb I (1984). "Origins of biliary copper". Hepatology. 4 (5): 867–70. doi:10.1002/hep.1840040512. PMID6479854.
Kingston IB, Kingston BL, Putnam FW (Apr 1980). "Primary structure of a histidine-rich proteolytic fragment of human ceruloplasmin. I. Amino acid sequence of the cyanogen bromide peptides". The Journal of Biological Chemistry. 255 (7): 2878–85. PMID6987229.
