Wikipedia

Ceruloplasmin

Ceruloplasmin(orcaeruloplasmin) is aferroxidaseenzymethat in humans is encoded by theCPgene.[5][6][7]

CP
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCP,CP-2, ceruloplasmin (ferroxidase), Ceruloplasmin, AB073614
External IDsOMIM:117700;MGI:88476;HomoloGene:75;GeneCards:CP;OMA:CP - orthologs
EC number1.16.3.1
Orthologs
SpeciesHumanMouse
Entrez

1356

12870

Ensembl

ENSG00000047457

ENSMUSG00000003617

UniProt

P00450

Q61147

RefSeq (mRNA)

NM_000096

NM_001042611
NM_001276248
NM_001276250
NM_007752
NM_001374677

RefSeq (protein)

NP_000087

NP_001263177
NP_001263179
NP_031778
NP_001361606

Location (UCSC)Chr 3: 149.16 – 149.22 MbChr 3: 20.01 – 20.06 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Ceruloplasmin is the majorcopper-carrying protein in the blood, and in addition plays a role iniron metabolism.It was first described in 1948.[8]Another protein,hephaestin,is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.

Function

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Ceruloplasmin (CP) is anenzyme(EC1.16.3.1) synthesized in the liver containing 6 atoms ofcopperin its structure.[9]Ceruloplasmin carries more than 95% of the total copper in healthy human plasma.[10]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 withtransferrin,which can carry iron only in the ferric state.[11]The molecular weight of human ceruloplasmin is reported to be 151kDa.

Despite extensive research, much is still unknown about the exact functions of CP, most of the functions are attributed to CP focus on the presence of the Cu centers. These include copper transport to deliver the Cu to extrahepatic tissues, amine oxidase activity that controls the level of biogenic amines in intestinal fluids and plasma, removal of oxygen and other free radicals from plasma, and theexport of ironfrom cells for transport throughtransferrin.[12]

Mutations have been known to disrupt the binding of copper to CP and will disrupt iron metabolism and cause aniron overload.

Ceruloplasmin is a relatively large enzyme (~10 nm); the larger size prevents the bound copper from being lost in aperson's urineduring transport.

Active site structure

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The multicopper active site of CP contains atype I(T1) mononuclear copper[12]site and a trinuclear copper center ~ 12-13 Å away (see figure 2). The tricopper center consists of twotype III(T3) coppers and onetype II(T2) copper ion. The two T3 copper ions are bridged by a hydroxide ligand while another hydroxide ligand links the T2 copper ion to the protein. The T1 center is bridged to the tricopper center by twohistidine(His1020, His1022) residues and oneCys(1021) residue. The substrate binds near the T1 center and is oxidized by the T1 Cu2+ion forming the reduced Cu+oxidation state. The reduced T1 Cu+then transfers the electron through the one Cys and two His bridging residues to the tricopper center. After four electrons have been transferred from the substrates to the copper centers, an O2binds at the tricopper center and undergoes a four-electron reduction to form two molecules of water.[12]

Figure 2: Close-up view of the human plasma CP active site consisting of the T1 copper center (left) and trinuclear copper center (right) showing the coordinating side chains. PDB code: 1KCW. Atom colors: Cu = grey; O = red; N = blue; S = yellow.

Regulation

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Acis-regulatory elementcalled theGAIT elementis involved in the selective translational silencing of the Ceruloplasmin transcript.[13] The silencing requires binding of a cytosolic inhibitor complex called IFN-gamma-activated inhibitor of translation (GAIT) to the GAIT element.[14]

Clinical significance

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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 thehepatocyteand 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.

Ceruloplasmin can be measured by means of a blood test;[15]this can be done usingimmunoassays.The sample is spun and separated; it is stored around 4 °C Celsius for three days. This test is to determine if there are signs of Wilson disease. Another test that can be done is a urine copper level test; this has been found to be less accurate than the blood test. A liver tissue test can be done as well.

Mutations in the ceruloplasmin gene (CP), which are very rare, can lead to the genetic diseaseaceruloplasminemia,characterized by hyperferritinemia withiron overload.In the brain, this iron overload may lead to characteristic neurologic signs and symptoms, such as cerebellarataxia,progressivedementia,andextrapyramidal signs.Excess iron may also deposit in the liver, pancreas, and retina, leading tocirrhosis,endocrineabnormalities, and loss of vision, respectively.

Deficiency

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Lower-than-normal ceruloplasmin levels may indicate the following:

Excess

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

Reference ranges

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

Reference ranges for blood tests,comparing blood content of ceruloplasmin (shown in gray) with other constituents.

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000047457–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000003617–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^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.Bibcode:1984PNAS...81..390T.doi:10.1073/pnas.81.2.390.PMC344682.PMID6582496.
  6. ^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.Bibcode:1986PNAS...83.5086K.doi:10.1073/pnas.83.14.5086.PMC323895.PMID2873574.
  7. ^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.S2CID45686258.
  8. ^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.
  9. ^O'Brien PJ, Bruce WR (2009).Endogenous Toxins: Targets for Disease Treatment and Prevention, 2 Volume Set.John Wiley & Sons. pp.405–6.ISBN978-3-527-32363-0.
  10. ^Hellman NE, Gitlin JD (2002). "Ceruloplasmin metabolism and function".Annual Review of Nutrition.22:439–58.doi:10.1146/annurev.nutr.22.012502.114457.PMID12055353.
  11. ^Song D, Dunaief JL (2013)."Retinal iron homeostasis in health and disease".Frontiers in Aging Neuroscience.5:24.doi:10.3389/fnagi.2013.00024.PMC3695389.PMID23825457.
  12. ^abcBertini I (2007).Biological Inorganic Chemistry.California, USA: University Science Books. pp.426–442.ISBN978-1-891389-43-6.
  13. ^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.PMC151701.PMID12588972.
  14. ^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.doi:10.1016/S1016-8478(23)13213-4.PMID16267389.
  15. ^"Ceruloplasmin Test: MedlinePlus Medical Test".medlineplus.gov.Retrieved2021-12-10.
  16. ^Scheinberg IH, Gitlin D (Oct 1952). "Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease)".Science.116(3018):484–5.Bibcode:1952Sci...116..484S.doi:10.1126/science.116.3018.484.PMID12994898.
  17. ^Gitlin JD (Sep 1998)."Aceruloplasminemia".Pediatric Research.44(3):271–6.doi:10.1203/00006450-199809000-00001.PMID9727700.
  18. ^Elkassabany NM, Meny GM, Doria RR, Marcucci C (Apr 2008)."Green plasma-revisited".Anesthesiology.108(4):764–5.doi:10.1097/ALN.0b013e3181672668.PMID18362615.
  19. ^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.S2CID843454.
  20. ^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.PMC2556376.PMID18534184.
  21. ^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.PMID16842975.S2CID38267889.
  22. ^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.PMC2596773.PMID19017404.

Further reading

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