Ceruloplasmin

CP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCP, CP-2, ceruloplasmin (ferroxidase), Ceruloplasmin, AB073614
External IDsOMIM: 117700 MGI: 88476 HomoloGene: 75 GeneCards: CP
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: 19.96 – 20.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the CP gene.[5][6][7]

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.[8] Another protein, hephaestin, is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.

Function

Ceruloplasmin (CP) is an enzyme (EC 1.16.3.1) synthesized in the liver containing 6 atoms of copper in 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 with transferrin, 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 the export of iron from cells for transport through transferrin.[12]

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

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

Active Site Structure

The multicopper active site of CP contains a trinuclear copper center with a type I (T1) mononuclear copper[12] ~ 12-13 Å away (see figure 2).  The trinuclear center consists of two type III (T3) coppers and one type 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 trinuclear center is bridged by two histidine (His1020, His1022) residues and one Cys(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 trinuclear copper center.  After four electrons have been transferred from the substrates to the copper centers, an O2 binds at the trinuclear 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

A cis-regulatory element called the GAIT element is 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

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.

Ceruloplasmin can be measured by means of a blood test;[15] this can be done using immunoassays . 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 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.

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

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000047457 - Ensembl, May 2017
  2. 1 2 3 GRCm38: 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. doi:10.1073/pnas.81.2.390. PMC 344682. PMID 6582496.
  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. doi:10.1073/pnas.83.14.5086. PMC 323895. PMID 2873574.
  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. PMID 3474786. S2CID 45686258.
  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. ISBN 978-3-527-32363-0.
  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. PMID 12055353.
  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. PMC 3695389. PMID 23825457.
  12. 1 2 3 Bertini, Ivano (2007). Biological Inorganic Chemistry. California, USA: University Science Books. pp. 426–442. ISBN 1-891389-43-2.
  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. PMC 151701. PMID 12588972.
  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. PMID 16267389.
  15. ↑ "Ceruloplasmin Test: MedlinePlus Medical Test". medlineplus.gov. Retrieved 2021-12-10.
  16. ↑ Scheinberg IH, Gitlin D (Oct 1952). "Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease)". Science. 116 (3018): 484–5. doi:10.1126/science.116.3018.484. PMID 12994898.
  17. ↑ Gitlin JD (Sep 1998). "Aceruloplasminemia". Pediatric Research. 44 (3): 271–6. doi:10.1203/00006450-199809000-00001. PMID 9727700.
  18. ↑ 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.
  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. PMID 18388036. S2CID 843454.
  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. PMC 2556376. PMID 18534184.
  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. PMID 16842975. S2CID 38267889.
  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. PMC 2596773. PMID 19017404.

Further reading


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