Ceruloplasmin

Ceruloplasmin (ferroxidase)
PDB rendering based on 1kcw.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1KCW, 2J5W, 4EJX, 4ENZ
Identifiers
Symbols	CP ; CP-2
External IDs	OMIM: 117700 MGI: 88476 HomoloGene: 75 GeneCards: CP Gene
EC number	1.16.3.1
Gene ontology Molecular function • ferroxidase activity • copper ion binding • chaperone binding Cellular component • extracellular region • extracellular space • lysosomal membrane • extracellular exosome • blood microparticle Biological process • copper ion transport • cellular iron ion homeostasis • transmembrane transport • oxidation-reduction process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1356	12870
Ensembl	ENSG00000047457	ENSMUSG00000003617
UniProt	P00450	Q61147
RefSeq (mRNA)	NM_000096	NM_001042611
RefSeq (protein)	NP_000087	NP_001263177
Location (UCSC)	Chr 3: 149.16 – 149.22 Mb	Chr 3: 19.96 – 20.01 Mb
PubMed search	[1]	[2]

Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the CP gene.

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. 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. Ceruloplasmin carries more than 95% of the total copper in healthy human plasma. 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. 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. The silencing requires binding of a cytosolic inhibitor complex called IFN-gamma-activated inhibitor of translation (GAIT) to the GAIT element.

Clinical significance

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

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)
• Delivery of copper into the lumen of the ER-Golgi network is absent in hepatocytes 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

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

• Wilson disease (a rare (UK incidence 1/100,000) copper storage disease)
• Menkes disease (Menkes kinky hair syndrome) (rare - UK incidence 1/100,000)
• Overdose of Vitamin C
• Copper deficiency
• Aceruloplasminemia

Excess

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

• copper toxicity / zinc deficiency
• pregnancy
• oral contraceptive pill use
• lymphoma
• acute and chronic inflammation (it is an acute-phase reactant)
• rheumatoid arthritis
• Angina
• Alzheimer's disease
• Schizophrenia
• Obsessive-compulsive disorder

Reference ranges

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

External links

• GeneReviews/NCBI/NIH/UW entry on Aceruloplasminemia
• OMIM entries on Aceruloplasminemia