Ceruloplasmin, the immune system
Most of this document was written for an M.D. interested in giving the Mitosynergy product to his patients. This post is a compilation of our discussions. Ceruloplasmin keeps copper and oxygen deep within its surface.
Here we have an image of ceruloplasm crystallized with just Cu, oxygen, glycerol and N-acetylglucosamine. No iron was used in this particular crystal structure. Sometimes X-ray crystallographers add other small molecules to enable purified proteins to form crystals. The images were produced by the software at rcsb.org. The image on the left is in “cartoon” mode. Only the backbone of the protein is shown. The image on the right is a “surface plot” of what a water molecule might see as it approaches the protein. Very little copper is visible from the surface. A region in the center of the protein with oxygen being complexed to copper is enlarged.
Ceruloplasmin, a ferroxidase I and more
Produced by the liver, transported by the blood, ceruloplasmin has been found in glial cells (CNS and retina) and Sertoli cells (testis) (Vashchenko 2013). Enzymatic reactions (Vashchenko 2013) include
- glutathione-peroxidase activities
- amine oxidase: biogenic amines, xenobiotic amine oxidase
Ceroplasmin’s multiple roles as a
- monoamine oxidase via copper
- an iron carrier
- copper carrier
was examined the hippocampus of the brains of ceruloplasmin knockout mice (Texel 2012). “Knockout” means that the gene has been removed from, or knocked out of, the genome.
Serotonin was one of the main neurotransmitters examined. The authors speculated that because iron is needed for the synthesis of serotonin and other monoamine neurotransmitters, ceruloplasmin might be a carrier of iron to the brain.
Ceruloplasmin deficiency induced by knock out of the gene decreased the iron, serotonin, and norepinephrine in the hippocampus (Texel 2012).
Corticosterone, a rodent regulator of energy, immune reactions, and stress responses, was increased in the ceruloplasmin knockout mice (Texel 2012). Some cognitive and motor function tests revealed an anxiety phenotype.
Ceruloplasmin constitutes the largest serum copper pool. Circulating ceruloplasmin is not absolutely required for copper delivery to tissues, demonstrating that other copper-binding molecules exist (Gulec 2014).
Transcription and translational control
- Mazumder and coworkers (2006) found that gamma interferon (INFγ) not only induced the transcription of ceruloplasmin mRNA but also regulated its translation to protein.
- The translational silencing of the ceruloplasmin mRNA in U937 monocytic cells was shown to require binding of a cytosolic inhibitor complex, IFN-Gamma-Activated Inhibitor of Translation (GAIT), to a specific GAIT element in the Cp 3’-UTR.
- The authors speculated that ceruloplasmin may have injurious consequences and require down-regulation. A delay in doing so could exacerbate macrophage induction of ceruloplasmin synthesis and delay or prevent the normal resolution of inflammation.
Suggestion of circulating copper deficient ceruloplasmin
Ranganathan and coworkers (2011) examined the impact of copper and iron excess and deficiency on the amount of ceruloplasmin in the serum of weaning rats. They not only looked at the amount of message but also the amount of translated protein and two enzyme activities of ceruloplasmin.
- amine oxidase (copper catalyzed)
This table is a simplified form of the original publication. Amine oxidase and ferroxidase activity are estimated from the fig 3 bar graph of the publication. The other values were copied from table 2.
|treatment||mRNA||Serum protein||Ferroxidase activity||Amine oxidase||Serum Cu, ppb||Serum Fe, mg/L|
|Fe def/Cu Extra||1.7||1.5||2||2.2||790||0.64|
|Fe D/Cu D||1.3||0.74||0||-0.04||20||0.33|
Highlighted cells are significantly different from the control.
- Dietary manipulations of Fe and Cu did not change the amount of message in a way that could be distinguished from population variance.
- Serum ceruloplasmin was changed in response to copper deficiency and Fe deficiency suggesting, but not proving, changes in mRNA translation outside the GAIT complex.
- The changes in enzyme activity, disproportional to the amount of protein, suggested the presence of circulating copper deficient ceruloplasmin.
- Amine oxidase, a Cu mediated reaction, increased with copper excess and Fe deficiency but not normal Cu.
- Ferroxidase activity was very sensitive to Cu deficiency but not Fe deficiency as long as dietary Cu was normal.
Ceruloplasmin and pathogen response
Gitlin and coworkers (1992) examined the influence of copper sufficiency and deficiency in the diets of rats exposed to inflammatory agents:
- lipopolysccharide (LPS)
- interleukin 1α.
LPS is a component of the cell wall of Gram negative bacteria and a pro-inflammatory agent.
IL-1α is a primary mediator of inflammation secreted by macrophages.
- Inflammatory agents like LPS and IL-1α increase ceruloplasmin transcripts
- TNFα and the GAIT complex interfere with those transcripts being translated into ceruloplasmin protein.
- Both IL-1α and LPS increased hepatic ceruloplasmin mRNA content.
- Ceruloplasmin protein was measured by the ELISA assay in normal and copper-deficient animals.
making apo ceruloplasmin
Neither mediator increased ceruloplasmin ferroxidase activity in the copper-deficient group. Newly synthesized ceruloplasmin secretion rates were the same for isolated hepatocytes from normal and copper-deficient rats despite little or no holo-ceruloplasmin synthesis in hepatocytes of copper-deficient rats.
Ceruloplasmin must pick up copper from somewhere
The authors concluded that hepatocyte copper content has no effect on hepatic ceruloplasmin-gene expression or ceruloplasmin biosynthesis. The incorporation of copper into newly synthesized ceruloplasmin is not a rate-limiting step in the biosynthesis or secretion of the apoprotein (copper free) from rat hepatocytes.
What we are seeing is that there might be a lot of ceruloplasmin in the blood that is copper depleted or apo because we see that dietary and injected copper can control the ferroxidase activity of ceruloplasmin (Gitlin 1992, Ranganathan 2011).
Loading ceruloplasmin with “proper copper” in the gut
In anotherblog we addressed how the Cu+ of Cu(I)NA2 might be absorbed. We looked at one model in which Cu+ is absorbed by Ctr1 in epithelial cells and then secreted into the blood by. ATP7A secreting Cu+ willy nilly into the blood stream just isn’t satisfying. Since ATP7A loads cderuloplasmin in the liver, why not in the blood?
Gitlin JD, Schroeder JJ, Lee-Ambrose LM, Cousins RJ.(1992) Mechanisms of caeruloplasmin biosynthesis in normal and copper-deficient rats. Biochem J. 282 ( Pt 3):835-9.
Gulec S, Collins JF. (2014) Molecular mediators governing iron-copper interactions. Annu Rev Nutr. 34:95-116.
Mazumder B, Sampath P, Fox PL.(2006)Translational control of ceruloplasmin gene expression: beyond the IRE. Biol Res. 39(1):59-66.
Prohaska JR.(2011) Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases). Adv Nutr.2(2):89-95
Ranganathan PN, Lu Y, Jiang L, Kim C, Collins JF. (2011) Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake. Blood. 118(11):3146-53.
Texel SJ, Camandola S, Ladenheim B, Rothman SM, Mughal MR, Unger EL, Cadet JL, Mattson MP. (2012)Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem.120(1):125-34
Vashchenko G, MacGillivray RT. (2013) Multi-copper oxidases and human iron metabolism. Nutrients.5(7):2289-313.
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