Ceruloplasmin
Mammalian protein found in Homo sapiens
- 3 min read
- 4 chapters
Related on Lably
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 (CP) 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. 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 (~10 nm); the larger size prevents the bound copper from being lost in a person's urine during transport.
Sign in to keep reading
3 more chapters are free with a Lably account.
Active site structure
The multicopper active site of CP contains a type I (T1) mononuclear copper site and a trinuclear copper center distant by ca.12-13 Å. The tricopper 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 T1 center is bridged to the tricopper center 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 tricopper center. After four electrons have been transferred from the substrates to the copper centers, an O2 binds at the tricopper center and undergoes a four-electron reduction to form two molecules of water.
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
- Zinc toxicity, due to induced copper deficiency
- 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 ER-Golgi network is absent in hepatocytes due to absent ATP7B (Wilson's disease)
Deficiency
Lower-than-normal ceruloplasmin levels may indicate the following:
- Wilson disease (a rare [UK incidence 2/100,000] copper storage disease).
- Menkes disease (Menkes kinky hair syndrome) (rare – UK incidence 1/100,000)
- Copper deficiency
- Aceruloplasminemia
- Zinc toxicity
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
Normal blood concentration of ceruloplasmin in humans is 20–50 mg/dL.