Ceruloplasmin (or caeruloplasmin) is officially known as ferroxidase or iron(II):oxygen oxidoreductase. It is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948.[1] Another protein, hephaestin, is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.
Function
It is an enzyme (EC 1.16.3.1) synthesized in the liver containing 6 atoms of copper in its structure. Ceruloplasmin carries 90% of the copper in our plasma. The other 10% is carried by albumin, albumin may be confused at times to have a greater importance as a copper carrier because it binds copper less tightly than ceruloplasmin. 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 only carry iron in the ferric state. The molecular weight of human ceruloplasmin is reported to be 151kDa.
Pathology
Like any other plasma protein, levels drop in patients with hepatic disease due to reduced synthesizing capabilities.
- Mechanisms of low ceruplasmin levels:
-
- Gene expression genetically low: aceruloplasminemia
- Copper levels are low in general:
- Malnutrition/trace metal deficiency in the food source
- Copper does not cross the intestinal barrier due to ATP7A deficiency in Menkes disease
- Delivery of copper into the lumen of the ER-Golgi network is absent in hepatocyte due to absent ATP7B in Wilson's disease.
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 can lead to the rare genetic human disease aceruloplasminemia, characterized by iron overload in the brain, liver, pancreas, and retina.
Interpretation
Decreased levels
Lower-than-normal ceruloplasmin levels may indicate:
Elevated levels
Greater-than-normal ceruloplasmin levels may indicate or be noticed in:
Reference ranges
References
- ^ Holmberg CG, Laurell C-B (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.
- ^ Scheinberg IH, Gitlin D (October 1952). "Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease)". Science 116 (3018): 484–5. doi:10.1126/science.116.3018.484. PMID 12994898.
- ^ Gitlin JD (1998). "Aceruloplasminemia". Pediatr. Res. 44 (3): 271–6. doi:10.1203/00006450-199809000-00001. PMID 9727700.
- ^ http://ang.sagepub.com/cgi/content/abstract/60/1/50?rss=1
- ^ Lutsenko S, Gupta A, Burkhead JL, Zuzel V (August 2008). "Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance". Arch. Biochem. Biophys. 476 (1): 22–32. doi:10.1016/j.abb.2008.05.005. PMID 18534184.
- ^ Wolf TL, Kotun J, Meador-Woodruff JH (September 2006). "Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia". Schizophr. Res. 86 (1-3): 167–71. doi:10.1016/j.schres.2006.05.027. PMID 16842975.
- ^ Virit O, Selek S, Bulut M, Savas HA, Celik H, Erel O, Herken H (2008). "High ceruloplasmin levels are associated with obsessive compulsive disorder: a case control study". Behav Brain Funct 4: 52. doi:10.1186/1744-9081-4-52. PMID 19017404.
Further reading
- Hellman NE, Gitlin JD (2002). "Ceruloplasmin metabolism and function". Annu. Rev. Nutr. 22: 439–58. doi:10.1146/annurev.nutr.22.012502.114457. PMID 12055353.
- Mazumder B, Seshadri V, Fox PL (2003). "Translational control by the 3'-UTR: the ends specify the means". Trends Biochem. Sci. 28 (2): 91–8. doi:10.1016/S0968-0004(03)00002-1. PMID 12575997.
- Giurgea N, Constantinescu MI, Stanciu R, et al. (2005). "Ceruloplasmin - acute-phase reactant or endogenous antioxidant? The case of cardiovascular disease". Med. Sci. Monit. 11 (2): RA48–51. PMID 15668644.
- Kingston IB, Kingston BL, Putnam FW (1978). "Chemical evidence that proteolytic cleavage causes the heterogeneity present in human ceruloplasmin preparations". Proc. Natl. Acad. Sci. U.S.A. 74 (12): 5377–81. doi:10.1073/pnas.74.12.5377. PMID 146197.
- Polosatov MV, Klimov PK, Masevich CG, et al. (1979). "Interaction of synthetic human big gastrin with blood proteins of man and animals". Acta hepato-gastroenterologica 26 (2): 154–9. PMID 463490.
- Schilsky ML, Stockert RJ, Pollard JW (1993). "Caeruloplasmin biosynthesis by the human uterus". Biochem. J. 288 ( Pt 2): 657–61. PMID 1463466.
- Walker FJ, Fay PJ (1990). "Characterization of an interaction between protein C and ceruloplasmin". J. Biol. Chem. 265 (4): 1834–6. PMID 2105310.
- Fleming RE, Gitlin JD (1990). "Primary structure of rat ceruloplasmin and analysis of tissue-specific gene expression during development". J. Biol. Chem. 265 (13): 7701–7. PMID 2332446.
- Yang FM, Friedrichs WE, Cupples RL, et al. (1990). "Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing". J. Biol. Chem. 265 (18): 10780–5. PMID 2355023.
- Koschinsky ML, Funk WD, van Oost BA, MacGillivray RT (1986). "Complete cDNA sequence of human preceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 83 (14): 5086–90. doi:10.1073/pnas.83.14.5086. PMID 2873574.
- Royle NJ, Irwin DM, Koschinsky ML, et al. (1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somat. Cell Mol. Genet. 13 (3): 285–92. doi:10.1007/BF01535211. PMID 3474786.
- Yang F, Naylor SL, Lum JB, et al. (1986). "Characterization, mapping, and expression of the human ceruloplasmin gene". Proc. Natl. Acad. Sci. U.S.A. 83 (10): 3257–61. doi:10.1073/pnas.83.10.3257. PMID 3486416.
- Mercer JF, Grimes A (1986). "Isolation of a human ceruloplasmin cDNA clone that includes the N-terminal leader sequence". FEBS Lett. 203 (2): 185–90. doi:10.1016/0014-5793(86)80739-6. PMID 3755405.
- Rask L, Valtersson C, Anundi H, et al. (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". Exp. Cell Res. 143 (1): 91–102. doi:10.1016/0014-4827(83)90112-X. PMID 6337857.
- Kressner MS, Stockert RJ, Morell AG, Sternlieb I (1984). "Origins of biliary copper". Hepatology 4 (5): 867–70. doi:10.1002/hep.1840040512. PMID 6479854.
- Takahashi N, Bauman RA, Ortel TL, et al. (1983). "Internal triplication in the structure of human ceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 80 (1): 115–9. doi:10.1073/pnas.80.1.115. PMID 6571985.
- Takahashi N, Ortel TL, Putnam FW (1984). "Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule". Proc. Natl. Acad. Sci. U.S.A. 81 (2): 390–4. doi:10.1073/pnas.81.2.390. PMID 6582496.
- Dwulet FE, Putnam FW (1981). "Complete amino acid sequence of a 50,000-dalton fragment of human ceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 78 (2): 790–4. doi:10.1073/pnas.78.2.790. PMID 6940148.
- Kingston IB, Kingston BL, Putnam FW (1980). "Primary structure of a histidine-rich proteolytic fragment of human ceruloplasmin. I. Amino acid sequence of the cyanogen bromide peptides". J. Biol. Chem. 255 (7): 2878–85. PMID 6987229.
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1kcw: X-RAY CRYSTAL STRUCTURE OF HUMAN CERULOPLASMIN AT 3.0 ANGSTROMS
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2j5w: CERULOPLASMIN REVISITED: STRUCTURAL AND FUNCTIONAL ROLES OF VARIOUS METAL CATION BINDING SITES
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