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{{PBB_Controls
{{Infobox_gene}}
| update_page = yes
'''Ceruloplasmin''' (or '''caeruloplasmin''') is a [[ferroxidase]] [[enzyme]] that in humans is encoded by the ''CP'' [[gene]].<ref name="pmid6582496">{{cite journal | vauthors = Takahashi N, Ortel TL, Putnam FW | title = Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 2 | pages = 390–4 | date = Jan 1984 | pmid = 6582496 | pmc = 344682 | doi = 10.1073/pnas.81.2.390 }}</ref><ref name="pmid2873574">{{cite journal | vauthors = Koschinsky ML, Funk WD, van Oost BA, MacGillivray RT | title = Complete cDNA sequence of human preceruloplasmin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 14 | pages = 5086–90 | date = Jul 1986 | pmid = 2873574 | pmc = 323895 | doi = 10.1073/pnas.83.14.5086 }}</ref><ref name="pmid3474786">{{cite journal | vauthors = Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL | title = Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively | journal = Somatic Cell and Molecular Genetics | volume = 13 | issue = 3 | pages = 285–92 | date = May 1987 | pmid = 3474786 | doi = 10.1007/BF01535211 }}</ref>
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = yes
}}
{{GNF_Protein_box
| image = PBB_Protein_CP_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1kcw.
| Name = Ceruloplasmin (ferroxidase)
| HGNCid = 2295
| Symbol = CP
| AltSymbols =; CP-2
| OMIM = 117700
| ECnumber = 
| Homologene = 75
| MGIid = 88476
| GeneAtlas_image1 = PBB_GE_CP_204846_at_tn.png
| Function = {{GNF_GO|id=GO:0004322 |text = ferroxidase activity}} {{GNF_GO|id=GO:0005375 |text = copper ion transmembrane transporter activity}} {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}  
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0006825 |text = copper ion transport}} {{GNF_GO|id=GO:0006878 |text = cellular copper ion homeostasis}} {{GNF_GO|id=GO:0006879 |text = cellular iron ion homeostasis}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1356
    | Hs_Ensembl = ENSG00000047457
    | Hs_RefseqProtein = NP_000087
    | Hs_RefseqmRNA = NM_000096
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 150374067
    | Hs_GenLoc_end = 150422269
    | Hs_Uniprot = P00450
    | Mm_EntrezGene = 12870
    | Mm_Ensembl = ENSMUSG00000003617
    | Mm_RefseqmRNA = NM_001042611
    | Mm_RefseqProtein = NP_001036076
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 20149205
    | Mm_GenLoc_end = 20200943
    | Mm_Uniprot = Q2F3J4
  }}
}}
{{CMG}}


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.<ref>{{cite journal | vauthors=Holmberg CG, Laurell CB | title=Investigations in serum copper. II. Isolation of the Copper containing protein, and a description of its properties | journal=Acta Chem Scand | year=1948 | volume=2 | pages=550–56 | doi=10.3891/acta.chem.scand.02-0550}}</ref> Another protein, [[hephaestin]], is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.


== Function ==


'''Ceruloplasmin''' (or '''caeruloplasmin''') is officially known as '''ferroxidase''' or '''iron(II):oxygen oxidoreductase'''.  
Ceruloplasmin is an [[enzyme]] ({{EC  number|1.16.3.1}}) synthesized in the liver containing 6 atoms of [[copper]] in its structure.<ref name="O'BrienBruce2009">{{cite book |vauthors=O'Brien PJ, Bruce WR | title = Endogenous Toxins: Targets for Disease Treatment and Prevention, 2 Volume Set | url = https://books.google.com/books?id=UaLR0RSuXvsC&pg=PA405 | year = 2009 | publisher = John Wiley & Sons|isbn=978-3-527-32363-0 | pages = 405–6 }}</ref> Ceruloplasmin carries more than 95% of the total copper in healthy human plasma.<ref name = "Hellman">{{cite journal | vauthors = Hellman NE, Gitlin JD | title = Ceruloplasmin metabolism and function | journal = Annual Review of Nutrition | volume = 22 | issue =  | pages = 439–58 | year = 2002 | pmid = 12055353 | doi = 10.1146/annurev.nutr.22.012502.114457 }}</ref> The rest is accounted for by macroglobulins. Ceruloplasmin exhibits a copper-dependent oxidase activity, which is associated with possible oxidation of Fe<sup>2+</sup> (ferrous iron) into Fe<sup>3+</sup> (ferric iron), therefore assisting in its transport in the plasma in association with [[transferrin]], which can carry iron only in the ferric state.<ref name = "Song">{{cite journal | vauthors = Song D, Dunaief JL | title = Retinal iron homeostasis in health and disease | journal = Frontiers in Aging Neuroscience | volume = 5 | issue =  | pages = 24 | year = 2013 | pmid = 23825457 | doi = 10.3389/fnagi.2013.00024 | pmc=3695389}}</ref>  The molecular weight of human ceruloplasmin is reported to be 151kDa.


==Function==
==Regulation==
It is an [[enzyme]] ({{EC  number|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 Fe<sup>2+</sup> (ferrous iron) into Fe<sup>3+</sup> (ferric iron), therefore assisting in its transport in the plasma in association with [[transferrin]], which can only carry iron in the ferric state.
 
A [[cis-regulatory element]] called the [[GAIT element]] is involved in the selective translational silencing of the Ceruloplasmin transcript.<ref name="pmid12588972">{{cite journal | vauthors = Sampath P, Mazumder B, Seshadri V, Fox PL | title = Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region | journal = Molecular and Cellular Biology | volume = 23 | issue = 5 | pages = 1509–19 | date = Mar 2003 | pmid = 12588972 | pmc = 151701 | doi = 10.1128/MCB.23.5.1509-1519.2003 }}</ref>
The silencing requires binding of a cytosolic inhibitor complex called IFN-gamma-activated inhibitor of translation (GAIT) to the GAIT element.<ref name="pmid16267389">{{cite journal | vauthors = Mazumder B, Sampath P, Fox PL | title = Regulation of macrophage ceruloplasmin gene expression: one paradigm of 3'-UTR-mediated translational control | journal = Molecules and Cells | volume = 20 | issue = 2 | pages = 167–72 | date = Oct 2005 | pmid = 16267389 | doi =  }}</ref>
 
== Clinical significance ==


==Pathology==
Like any other plasma protein, levels drop in patients with hepatic disease due to reduced synthesizing capabilities.
Like any other plasma protein, levels drop in patients with hepatic disease due to reduced synthesizing capabilities.


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.
Mechanisms of low ceruloplasmin 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 ([[Menkes disease]] and [[Occipital horn syndrome]])
* Delivery of copper into the lumen of the [[Endoplasmic reticulum|ER]]-[[Golgi apparatus|Golgi]] network is absent in [[hepatocyte]]s due to absent [[ATP7B]] ([[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 (''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 ===


==Interpretation==
Lower-than-normal ceruloplasmin levels may indicate the following:
===Decreased levels===
* [[Wilson disease]] (a rare (UK incidence 2/100,000) copper storage disease).<ref>{{cite journal | vauthors = Scheinberg IH, Gitlin D | title = Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease) | journal = Science | volume = 116 | issue = 3018 | pages = 484–5 | date = Oct 1952 | pmid = 12994898 | doi = 10.1126/science.116.3018.484 }}</ref>
Lower-than-normal ceruloplasmin levels may indicate:
* [[Menkes disease]] (Menkes kinky hair syndrome) (rare – UK incidence 1/100,000)
* [[Menkes disease]] (Menke's kinky hair syndrome) (very rare)
* [[Wilson's disease]] (a rare copper storage disease)
* Overdose of [[Vitamin C|vitamin C]]
* [[Copper]] deficiency
* [[Copper]] deficiency
* [[Aceruloplasminemia]]
* [[Aceruloplasminemia]]<ref>{{cite journal | vauthors = Gitlin JD | title = Aceruloplasminemia | journal = Pediatric Research | volume = 44 | issue = 3 | pages = 271–6 | date = Sep 1998 | pmid = 9727700 | doi = 10.1203/00006450-199809000-00001 }}</ref>
 
=== Excess ===


===Elevated levels===
Greater-than-normal ceruloplasmin levels may indicate or be noticed in:
Greater-than-normal ceruloplasmin levels may indicate:
* [[copper toxicity]] / [[zinc deficiency]]
* [[pregnancy]]
* [[pregnancy]]
* [[oral contraceptive pill]] use<ref name="pmid18362615">{{cite journal | vauthors = Elkassabany NM, Meny GM, Doria RR, Marcucci C | title = Green plasma-revisited | journal = Anesthesiology | volume = 108 | issue = 4 | pages = 764–5 | date = Apr 2008 | pmid = 18362615 | doi = 10.1097/ALN.0b013e3181672668 }}</ref>
* [[lymphoma]]
* [[lymphoma]]
* acute and chronic [[inflammation]] (it is an [[acute-phase reaction|acute-phase reactant]])
* acute and chronic [[inflammation]] (it is an [[acute-phase reaction|acute-phase reactant]])
* [[rheumatoid arthritis]]
* [[rheumatoid arthritis]]
* [[Angina pectoris|Angina]]<ref name="pmid18388036">{{cite journal | vauthors = 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 | title = Ceruloplasmin is a better predictor of the long-term prognosis compared with fibrinogen, CRP, and IL-6 in patients with severe unstable angina | journal = Angiology | volume = 60 | issue = 1 | pages = 50–9 | year = 2009 | pmid = 18388036 | doi = 10.1177/0003319708314249 }}</ref>
* [[Alzheimer's disease]]<ref name="pmid18534184">{{cite journal | vauthors = Lutsenko S, Gupta A, Burkhead JL, Zuzel V | title = Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance | journal = Archives of Biochemistry and Biophysics | volume = 476 | issue = 1 | pages = 22–32 | date = Aug 2008 | pmid = 18534184 | pmc = 2556376 | doi = 10.1016/j.abb.2008.05.005 }}</ref>
* [[Schizophrenia]]<ref name="pmid16842975">{{cite journal | vauthors = Wolf TL, Kotun J, Meador-Woodruff JH | title = Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia | journal = Schizophrenia Research | volume = 86 | issue = 1–3 | pages = 167–71 | date = Sep 2006 | pmid = 16842975 | doi = 10.1016/j.schres.2006.05.027 }}</ref>
* [[Obsessive-compulsive disorder]]<ref name="pmid19017404">{{cite journal | vauthors = Virit O, Selek S, Bulut M, Savas HA, Celik H, Erel O, Herken H | title = High ceruloplasmin levels are associated with obsessive compulsive disorder: a case control study | journal = Behavioral and Brain Functions | volume = 4 | issue =  | pages = 52 | year = 2008 | pmid = 19017404 | pmc = 2596773 | doi = 10.1186/1744-9081-4-52 }}</ref>
=== Reference ranges ===


==References==
Normal blood concentration of ceruloplasmin in humans is 20-50 mg/dL.[[File:Blood values sorted by mass and molar concentration.png|thumb|left|450px|[[Reference ranges for blood tests]], comparing blood content of ceruloplasmin (shown in gray) with other constituents.]]
{{reflist}}
{{Clear}}
==Further reading==
 
{{refbegin | 2}}
== References ==
{{PBB_Further_reading
{{reflist|35em}}
| citations =
 
*{{cite journal  | author=Gitlin JD |title=Aceruloplasminemia. |journal=Pediatr. Res. |volume=44 |issue= 3 |pages= 271-6 |year= 1998 |pmid= 9727700 |doi=  10.1203/00006450-199809000-00001}}
== Further reading ==
*{{cite journal | author=Hellman NE, Gitlin JD |title=Ceruloplasmin metabolism and function. |journal=Annu. Rev. Nutr. |volume=22 |issue=  |pages= 439-58 |year= 2002 |pmid= 12055353 |doi= 10.1146/annurev.nutr.22.012502.114457 }}
{{refbegin|35em}}
*{{cite journal | author=Mazumder B, Seshadri V, Fox PL |title=Translational control by the 3'-UTR: the ends specify the means. |journal=Trends Biochem. Sci. |volume=28 |issue= 2 |pages= 91-8 |year= 2003 |pmid= 12575997 |doi= 10.1016/S0968-0004(03)00002-1}}
* {{cite journal | vauthors = Hellman NE, Gitlin JD | title = Ceruloplasmin metabolism and function | journal = Annual Review of Nutrition | volume = 22 | issue =  | pages = 439–58 | year = 2002 | pmid = 12055353 | doi = 10.1146/annurev.nutr.22.012502.114457 }}
*{{cite journal | author=Giurgea N, Constantinescu MI, Stanciu R, ''et al.'' |title=Ceruloplasmin - acute-phase reactant or endogenous antioxidant? The case of cardiovascular disease. |journal=Med. Sci. Monit. |volume=11 |issue= 2 |pages= RA48-51 |year= 2005 |pmid= 15668644 |doi=  }}
* {{cite journal | vauthors = Mazumder B, Seshadri V, Fox PL | title = Translational control by the 3'-UTR: the ends specify the means | journal = Trends in Biochemical Sciences | volume = 28 | issue = 2 | pages = 91–8 | date = Feb 2003 | pmid = 12575997 | doi = 10.1016/S0968-0004(03)00002-1 }}
*{{cite journal | author=Kingston IB, Kingston BL, Putnam FW |title=Chemical evidence that proteolytic cleavage causes the heterogeneity present in human ceruloplasmin preparations. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=74 |issue= 12 |pages= 5377-81 |year= 1978 |pmid= 146197 |doi= }}
* {{cite journal | vauthors = Giurgea N, Constantinescu MI, Stanciu R, Suciu S, Muresan A | title = Ceruloplasmin - acute-phase reactant or endogenous antioxidant? The case of cardiovascular disease | journal = Medical Science Monitor | volume = 11 | issue = 2 | pages = RA48-51 | date = Feb 2005 | pmid = 15668644 | doi =  }}
*{{cite journal | author=Polosatov MV, Klimov PK, Masevich CG, ''et al.'' |title=Interaction of synthetic human big gastrin with blood proteins of man and animals. |journal=Acta hepato-gastroenterologica |volume=26 |issue= 2 |pages= 154-9 |year= 1979 |pmid= 463490 |doi=  }}
* {{cite journal | vauthors = Kingston IB, Kingston BL, Putnam FW | title = Chemical evidence that proteolytic cleavage causes the heterogeneity present in human ceruloplasmin preparations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 12 | pages = 5377–81 | date = Dec 1977 | pmid = 146197 | pmc = 431726 | doi = 10.1073/pnas.74.12.5377 }}
*{{cite journal | author=Schilsky ML, Stockert RJ, Pollard JW |title=Caeruloplasmin biosynthesis by the human uterus. |journal=Biochem. J. |volume=288 ( Pt 2) |issue= |pages= 657-61 |year= 1993 |pmid= 1463466 |doi=  }}
* {{cite journal | vauthors = Polosatov MV, Klimov PK, Masevich CG, Samartsev MA, Wünsch E | title = Interaction of synthetic human big gastrin with blood proteins of man and animals | journal = Acta Hepato-Gastroenterologica | volume = 26 | issue = 2 | pages = 154–9 | date = Apr 1979 | pmid = 463490 | doi =  }}
*{{cite journal | author=Walker FJ, Fay PJ |title=Characterization of an interaction between protein C and ceruloplasmin. |journal=J. Biol. Chem. |volume=265 |issue= 4 |pages= 1834-6 |year= 1990 |pmid= 2105310 |doi=  }}
* {{cite journal | vauthors = Schilsky ML, Stockert RJ, Pollard JW | title = Caeruloplasmin biosynthesis by the human uterus | journal = The Biochemical Journal | volume = 288 | issue = 2 | pages = 657–61 | date = Dec 1992 | pmid = 1463466 | pmc = 1132061 | doi =  10.1042/bj2880657}}
*{{cite journal | author=Fleming RE, Gitlin JD |title=Primary structure of rat ceruloplasmin and analysis of tissue-specific gene expression during development. |journal=J. Biol. Chem. |volume=265 |issue= 13 |pages= 7701-7 |year= 1990 |pmid= 2332446 |doi=  }}
* {{cite journal | vauthors = Walker FJ, Fay PJ | title = Characterization of an interaction between protein C and ceruloplasmin | journal = The Journal of Biological Chemistry | volume = 265 | issue = 4 | pages = 1834–6 | date = Feb 1990 | pmid = 2105310 | doi =  }}
*{{cite journal | author=Yang FM, Friedrichs WE, Cupples RL, ''et al.'' |title=Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing. |journal=J. Biol. Chem. |volume=265 |issue= 18 |pages= 10780-5 |year= 1990 |pmid= 2355023 |doi=  }}
* {{cite journal | vauthors = Fleming RE, Gitlin JD | title = Primary structure of rat ceruloplasmin and analysis of tissue-specific gene expression during development | journal = The Journal of Biological Chemistry | volume = 265 | issue = 13 | pages = 7701–7 | date = May 1990 | pmid = 2332446 | doi =  }}
*{{cite journal | author=Koschinsky ML, Funk WD, van Oost BA, MacGillivray RT |title=Complete cDNA sequence of human preceruloplasmin. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue= 14 |pages= 5086-90 |year= 1986 |pmid= 2873574 |doi=  10.1073/pnas.83.14.5086}}
* {{cite journal | vauthors = Yang FM, Friedrichs WE, Cupples RL, Bonifacio MJ, Sanford JA, Horton WA, Bowman BH | title = Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing | journal = The Journal of Biological Chemistry | volume = 265 | issue = 18 | pages = 10780–5 | date = Jun 1990 | pmid = 2355023 | doi =  }}
*{{cite journal  | author=Royle NJ, Irwin DM, Koschinsky ML, ''et al.'' |title=Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively. |journal=Somat. Cell Mol. Genet. |volume=13 |issue= 3 |pages= 285-92 |year= 1987 |pmid= 3474786 |doi=  10.1007/BF01535211}}
* {{cite journal | vauthors = Yang F, Naylor SL, Lum JB, Cutshaw S, McCombs JL, Naberhaus KH, McGill JR, Adrian GS, Moore CM, Barnett DR | title = Characterization, mapping, and expression of the human ceruloplasmin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 10 | pages = 3257–61 | date = May 1986 | pmid = 3486416 | pmc = 323492 | doi = 10.1073/pnas.83.10.3257 }}
*{{cite journal  | author=Yang F, Naylor SL, Lum JB, ''et al.'' |title=Characterization, mapping, and expression of the human ceruloplasmin gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue= 10 |pages= 3257-61 |year= 1986 |pmid= 3486416 |doi= 10.1073/pnas.83.10.3257}}
* {{cite journal | vauthors = Mercer JF, Grimes A | title = Isolation of a human ceruloplasmin cDNA clone that includes the N-terminal leader sequence | journal = FEBS Letters | volume = 203 | issue = 2 | pages = 185–90 | date = Jul 1986 | pmid = 3755405 | doi = 10.1016/0014-5793(86)80739-6 }}
*{{cite journal | author=Mercer JF, Grimes A |title=Isolation of a human ceruloplasmin cDNA clone that includes the N-terminal leader sequence. |journal=FEBS Lett. |volume=203 |issue= 2 |pages= 185-90 |year= 1986 |pmid= 3755405 |doi= 10.1016/0014-5793(86)80739-6}}
* {{cite journal | vauthors = Rask L, Valtersson C, Anundi H, Kvist S, Eriksson U, Dallner G, Peterson PA | title = Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens | journal = Experimental Cell Research | volume = 143 | issue = 1 | pages = 91–102 | date = Jan 1983 | pmid = 6337857 | doi = 10.1016/0014-4827(83)90112-X }}
*{{cite journal | author=Rask L, Valtersson C, Anundi H, ''et al.'' |title=Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens. |journal=Exp. Cell Res. |volume=143 |issue= 1 |pages= 91-102 |year= 1983 |pmid= 6337857 |doi= 10.1016/0014-4827(83)90112-X}}
* {{cite journal | vauthors = Kressner MS, Stockert RJ, Morell AG, Sternlieb I | title = Origins of biliary copper | journal = Hepatology | volume = 4 | issue = 5 | pages = 867–70 | year = 1984 | pmid = 6479854 | doi = 10.1002/hep.1840040512 }}
*{{cite journal | author=Kressner MS, Stockert RJ, Morell AG, Sternlieb I |title=Origins of biliary copper. |journal=Hepatology |volume=4 |issue= 5 |pages= 867-70 |year= 1984 |pmid= 6479854 |doi= }}
* {{cite journal | vauthors = Takahashi N, Bauman RA, Ortel TL, Dwulet FE, Wang CC, Putnam FW | title = Internal triplication in the structure of human ceruloplasmin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 1 | pages = 115–9 | date = Jan 1983 | pmid = 6571985 | pmc = 393320 | doi = 10.1073/pnas.80.1.115 }}
*{{cite journal | author=Takahashi N, Bauman RA, Ortel TL, ''et al.'' |title=Internal triplication in the structure of human ceruloplasmin. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=80 |issue= 1 |pages= 115-9 |year= 1983 |pmid= 6571985 |doi= 10.1073/pnas.80.1.115}}
* {{cite journal | vauthors = Dwulet FE, Putnam FW | title = Complete amino acid sequence of a 50,000-dalton fragment of human ceruloplasmin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 2 | pages = 790–4 | date = Feb 1981 | pmid = 6940148 | pmc = 319888 | doi = 10.1073/pnas.78.2.790 }}
*{{cite journal | author=Takahashi N, Ortel TL, Putnam FW |title=Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=81 |issue= 2 |pages= 390-4 |year= 1984 |pmid= 6582496 |doi=  10.1073/pnas.81.2.390}}
* {{cite journal | vauthors = Kingston IB, Kingston BL, Putnam FW | title = Primary structure of a histidine-rich proteolytic fragment of human ceruloplasmin. I. Amino acid sequence of the cyanogen bromide peptides | journal = The Journal of Biological Chemistry | volume = 255 | issue = 7 | pages = 2878–85 | date = Apr 1980 | pmid = 6987229 | doi =  }}
*{{cite journal  | author=Dwulet FE, Putnam FW |title=Complete amino acid sequence of a 50,000-dalton fragment of human ceruloplasmin. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=78 |issue= 2 |pages= 790-4 |year= 1981 |pmid= 6940148 |doi= 10.1073/pnas.78.2.790}}
*{{cite journal | author=Kingston IB, Kingston BL, Putnam FW |title=Primary structure of a histidine-rich proteolytic fragment of human ceruloplasmin. I. Amino acid sequence of the cyanogen bromide peptides. |journal=J. Biol. Chem. |volume=255 |issue= 7 |pages= 2878-85 |year= 1980 |pmid= 6987229 |doi=  }}
}}
{{refend}}
{{refend}}


{{Other oxidoreductases}}
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1493/  GeneReviews/NCBI/NIH/UW entry on Aceruloplasminemia]
* [https://www.ncbi.nlm.nih.gov/omim/117700,604290,117700,604290  OMIM entries on Aceruloplasminemia]
 
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Latest revision as of 16:03, 6 March 2018

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Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the CP gene.[1][2][3]

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.

Function

Ceruloplasmin is an enzyme (EC 1.16.3.1) 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.

Mechanisms of low ceruloplasmin levels:

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:

Excess

Greater-than-normal ceruloplasmin levels may indicate or be noticed in:

Reference ranges

Normal blood concentration of ceruloplasmin in humans is 20-50 mg/dL.

File:Blood values sorted by mass and molar concentration.png
Reference ranges for blood tests, comparing blood content of ceruloplasmin (shown in gray) with other constituents.

References

  1. ↑ Takahashi N, Ortel TL, Putnam FW (Jan 1984). "Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule". Proceedings of the National Academy of Sciences of the United States of America. 81 (2): 390–4. doi:10.1073/pnas.81.2.390. PMC 344682. PMID 6582496.
  2. ↑ Koschinsky ML, Funk WD, van Oost BA, MacGillivray RT (Jul 1986). "Complete cDNA sequence of human preceruloplasmin". Proceedings of the National Academy of Sciences of the United States of America. 83 (14): 5086–90. doi:10.1073/pnas.83.14.5086. PMC 323895. PMID 2873574.
  3. ↑ 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. PMID 3474786.
  4. ↑ 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.
  5. ↑ O'Brien PJ, Bruce WR (2009). Endogenous Toxins: Targets for Disease Treatment and Prevention, 2 Volume Set. John Wiley & Sons. pp. 405–6. ISBN 978-3-527-32363-0.
  6. ↑ Hellman NE, Gitlin JD (2002). "Ceruloplasmin metabolism and function". Annual Review of Nutrition. 22: 439–58. doi:10.1146/annurev.nutr.22.012502.114457. PMID 12055353.
  7. ↑ Song D, Dunaief JL (2013). "Retinal iron homeostasis in health and disease". Frontiers in Aging Neuroscience. 5: 24. doi:10.3389/fnagi.2013.00024. PMC 3695389. PMID 23825457.
  8. ↑ Sampath P, Mazumder B, Seshadri V, Fox PL (Mar 2003). "Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region". Molecular and Cellular Biology. 23 (5): 1509–19. doi:10.1128/MCB.23.5.1509-1519.2003. PMC 151701. PMID 12588972.
  9. ↑ Mazumder B, Sampath P, Fox PL (Oct 2005). "Regulation of macrophage ceruloplasmin gene expression: one paradigm of 3'-UTR-mediated translational control". Molecules and Cells. 20 (2): 167–72. PMID 16267389.
  10. ↑ Scheinberg IH, Gitlin D (Oct 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.
  11. ↑ Gitlin JD (Sep 1998). "Aceruloplasminemia". Pediatric Research. 44 (3): 271–6. doi:10.1203/00006450-199809000-00001. PMID 9727700.
  12. ↑ Elkassabany NM, Meny GM, Doria RR, Marcucci C (Apr 2008). "Green plasma-revisited". Anesthesiology. 108 (4): 764–5. doi:10.1097/ALN.0b013e3181672668. PMID 18362615.
  13. ↑ 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. PMID 18388036.
  14. ↑ Lutsenko S, Gupta A, Burkhead JL, Zuzel V (Aug 2008). "Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance". Archives of Biochemistry and Biophysics. 476 (1): 22–32. doi:10.1016/j.abb.2008.05.005. PMC 2556376. PMID 18534184.
  15. ↑ Wolf TL, Kotun J, Meador-Woodruff JH (Sep 2006). "Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia". Schizophrenia Research. 86 (1–3): 167–71. doi:10.1016/j.schres.2006.05.027. PMID 16842975.
  16. ↑ 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". Behavioral and Brain Functions. 4: 52. doi:10.1186/1744-9081-4-52. PMC 2596773. PMID 19017404.

Further reading

External links

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