| Ceruloplasmin (ferroxidase) |
PDB rendering based on 1kcw. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1KCW, 2J5W
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| 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
• oxidoreductase activity
• metal ion binding
• chaperone binding
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| Cellular component |
• extracellular region
• extracellular region
• extracellular space
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| Biological process |
• ion transport
• copper ion transport
• cellular iron ion homeostasis
• transmembrane transport
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
1356 |
12870 |
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| Ensembl |
ENSG00000047457 |
ENSMUSG00000003617 |
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| UniProt |
P00450 |
Q61147 |
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| RefSeq (mRNA) |
NM_000096.3 |
NM_001042611.1 |
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| RefSeq (protein) |
NP_000087.1 |
NP_001036076.1 |
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| Location (UCSC) |
Chr 3:
148.88 – 148.94 Mb |
Chr 3:
19.86 – 19.91 Mb |
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| PubMed search |
[1] |
[2] |
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Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the CP gene.[1][2][3]
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.[4] Another protein, hephaestin, is noted for its homology to ceruloplasmin, and also participates in iron and probably copper metabolism.
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Contents
- 1 Function
- 2 Pathology
- 3 Interpretation
- 3.1 Decreased levels
- 3.2 Elevated levels
- 3.3 Reference ranges
- 4 Regulation
- 5 References
- 6 Further reading
- 7 External links
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Function
It is an enzyme (EC 1.16.3.1) synthesized in the liver containing 6 atoms of copper in its structure. Ceruloplasmin carries about 70% of the total copper in human plasma while albumin carries about 15%. The rest is accounted for by macroglobulins. Albumin may be confused at times to have a greater importance as a copper carrier because it binds copper less tightly than ceruloplasmin. 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.
Pathology
Like any other plasma protein, levels drop in patients with hepatic disease due to reduced synthesizing capabilities.
Mechanisms of low ceruplasmin 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.
Interpretation
Decreased levels
Lower-than-normal ceruloplasmin levels may indicate:
- Wilson disease (a rare copper storage disease)[5]
- Menkes disease (Menke kinky hair syndrome) (very rare)
- Overdose of Vitamin C
- Copper deficiency
- Aceruloplasminemia[6]
Elevated levels
Greater-than-normal ceruloplasmin levels may indicate or be noticed in:
- pregnancy
- oral contraceptive pill use [7]
- lymphoma
- acute and chronic inflammation (it is an acute-phase reactant)
- rheumatoid arthritis
- Angina [8]
- Alzheimer's disease[9]
- Schizophrenia[10]
- Obsessive-compulsive disorder[11]
Reference ranges
Reference ranges for blood tests, comparing blood content of ceruloplasmin (shown in gray) with other constituents.
Regulation
A cis-regulatory element called the GAIT element is involved in the selective translational silencing of the Ceruloplasmin transcript.[12] The silencing requires binding of a cytosolic inhibitor complex called IFN-gamma-activated inhibitor of translation (GAIT) to the GAIT element.[13]
References
- ^ Takahashi N, Ortel TL, Putnam FW (January 1984). "Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule". Proc. Natl. Acad. Sci. U.S.A. 81 (2): 390–4. DOI:10.1073/pnas.81.2.390. PMC 344682. PMID 6582496. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=344682.
- ^ Koschinsky ML, Funk WD, van Oost BA, MacGillivray RT (July 1986). "Complete cDNA sequence of human preceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 83 (14): 5086–90. DOI:10.1073/pnas.83.14.5086. PMC 323895. PMID 2873574. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=323895.
- ^ 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". Somat. Cell Mol. Genet. 13 (3): 285–92. DOI:10.1007/BF01535211. PMID 3474786.
- ^ Holmberg CG, Laurell C-B (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.
- ^ Scheinberg IH, Gitlin D (October 1952). "Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson disease)". Science 116 (3018): 484–5. DOI:10.1126/science.116.3018.484. PMID 12994898.
- ^ Gitlin JD (1998). "Aceruloplasminemia". Pediatr. Res. 44 (3): 271–6. DOI:10.1203/00006450-199809000-00001. PMID 9727700.
- ^ http://journals.lww.com/anesthesiology/Fulltext/2008/04000/Green_Plasma_Revisited.35.aspx
- ^ http://ang.sagepub.com/cgi/content/abstract/60/1/50?rss=1
- ^ Lutsenko S, Gupta A, Burkhead JL, Zuzel V (August 2008). "Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance". Arch. Biochem. Biophys. 476 (1): 22–32. DOI:10.1016/j.abb.2008.05.005. PMC 2556376. PMID 18534184. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2556376.
- ^ Wolf TL, Kotun J, Meador-Woodruff JH (September 2006). "Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia". Schizophr. Res. 86 (1–3): 167–71. DOI:10.1016/j.schres.2006.05.027. PMID 16842975.
- ^ 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". Behav Brain Funct 4: 52. DOI:10.1186/1744-9081-4-52. PMC 2596773. PMID 19017404. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2596773.
- ^ Sampath, P; Mazumder B, Seshadri V, Fox PL (2003). "Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3' untranslated region". Mol Cell Biol 23 (5): 1509–1519. DOI:10.1128/MCB.23.5.1509-1519.2003. PMC 151701. PMID 12588972. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151701.
- ^ Mazumder B, Sampath P, Fox PL (2005). "Regulation of macrophage ceruloplasmin gene expression: one paradigm of 3'-UTR-mediated translational control". Mol Cells 20 (2): 167–72. PMID 16267389.
Further reading
- Hellman NE, Gitlin JD (2002). "Ceruloplasmin metabolism and function". Annu. Rev. Nutr. 22: 439–58. DOI:10.1146/annurev.nutr.22.012502.114457. PMID 12055353.
- Mazumder B, Seshadri V, Fox PL (2003). "Translational control by the 3'-UTR: the ends specify the means". Trends Biochem. Sci. 28 (2): 91–8. DOI:10.1016/S0968-0004(03)00002-1. PMID 12575997.
- Giurgea N, Constantinescu MI, Stanciu R, et al. (2005). "Ceruloplasmin - acute-phase reactant or endogenous antioxidant? The case of cardiovascular disease". Med. Sci. Monit. 11 (2): RA48–51. PMID 15668644.
- Kingston IB, Kingston BL, Putnam FW (1978). "Chemical evidence that proteolytic cleavage causes the heterogeneity present in human ceruloplasmin preparations". Proc. Natl. Acad. Sci. U.S.A. 74 (12): 5377–81. DOI:10.1073/pnas.74.12.5377. PMC 431726. PMID 146197. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=431726.
- Polosatov MV, Klimov PK, Masevich CG, et al. (1979). "Interaction of synthetic human big gastrin with blood proteins of man and animals". Acta hepato-gastroenterologica 26 (2): 154–9. PMID 463490.
- Schilsky ML, Stockert RJ, Pollard JW (1993). "Caeruloplasmin biosynthesis by the human uterus". Biochem. J. 288 (2): 657–61. PMC 1132061. PMID 1463466. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1132061.
- Walker FJ, Fay PJ (1990). "Characterization of an interaction between protein C and ceruloplasmin". J. Biol. Chem. 265 (4): 1834–6. PMID 2105310.
- Fleming RE, Gitlin JD (1990). "Primary structure of rat ceruloplasmin and analysis of tissue-specific gene expression during development". J. Biol. Chem. 265 (13): 7701–7. PMID 2332446.
- Yang FM, Friedrichs WE, Cupples RL, et al. (1990). "Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing". J. Biol. Chem. 265 (18): 10780–5. PMID 2355023.
- Yang F, Naylor SL, Lum JB, et al. (1986). "Characterization, mapping, and expression of the human ceruloplasmin gene". Proc. Natl. Acad. Sci. U.S.A. 83 (10): 3257–61. DOI:10.1073/pnas.83.10.3257. PMC 323492. PMID 3486416. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=323492.
- Mercer JF, Grimes A (1986). "Isolation of a human ceruloplasmin cDNA clone that includes the N-terminal leader sequence". FEBS Lett. 203 (2): 185–90. DOI:10.1016/0014-5793(86)80739-6. PMID 3755405.
- Rask L, Valtersson C, Anundi H, et al. (1983). "Subcellular localization in normal and vitamin A-deficient rat liver of vitamin A serum transport proteins, albumin, ceruloplasmin and class I major histocompatibility antigens". Exp. Cell Res. 143 (1): 91–102. DOI:10.1016/0014-4827(83)90112-X. PMID 6337857.
- Kressner MS, Stockert RJ, Morell AG, Sternlieb I (1984). "Origins of biliary copper". Hepatology 4 (5): 867–70. DOI:10.1002/hep.1840040512. PMID 6479854.
- Takahashi N, Bauman RA, Ortel TL, et al. (1983). "Internal triplication in the structure of human ceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 80 (1): 115–9. DOI:10.1073/pnas.80.1.115. PMC 393320. PMID 6571985. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=393320.
- Dwulet FE, Putnam FW (1981). "Complete amino acid sequence of a 50,000-dalton fragment of human ceruloplasmin". Proc. Natl. Acad. Sci. U.S.A. 78 (2): 790–4. DOI:10.1073/pnas.78.2.790. PMC 319888. PMID 6940148. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=319888.
- Kingston IB, Kingston BL, Putnam FW (1980). "Primary structure of a histidine-rich proteolytic fragment of human ceruloplasmin. I. Amino acid sequence of the cyanogen bromide peptides". J. Biol. Chem. 255 (7): 2878–85. PMID 6987229.
External links
- GeneReviews/NCBI/NIH/UW entry on Aceruloplasminemia
- OMIM entries on Aceruloplasminemia
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PDB gallery
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1kcw: X-RAY CRYSTAL STRUCTURE OF HUMAN CERULOPLASMIN AT 3.0 ANGSTROMS
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2j5w: CERULOPLASMIN REVISITED: STRUCTURAL AND FUNCTIONAL ROLES OF VARIOUS METAL CATION BINDING SITES
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Other oxidoreductases (EC 1.15-1.21)
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| 1.15: Acting on superoxide as acceptor |
Superoxide dismutase (SOD1, SOD2, SOD3)
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| 1.16: Oxidizing metal ions |
Ceruloplasmin
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| 1.17: Acting on CH or CH2 groups |
Xanthine oxidase - Ribonucleotide reductase - 4-hydroxy-3-methylbut-2-enyl diphosphate reductase
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| 1.18: Acting on iron-sulfur proteins as donors |
Nitrogenase
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| 1.19: Acting on reduced flavodoxin as donor |
Nitrogenase (flavodoxin)
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| 1.20: Acting on phosphorus or arsenic in donors |
Glutaredoxin (GLRX, GLRX2, GLRX3, GLRX5)
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| 1.21: Acting on X-H and Y-H to form an X-Y bond |
Isopenicillin-N synthase
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 2.7.10
- 2.7.11-12
- 3.1
- 3.1.3.48
- 3.4.21
- 4.1
- 5.1
- 6.1-3
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Proteins: carrier proteins
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| Fatty acid |
FABP1 · FABP2 · FABP3 · FABP4 · FABP5 · FABP6 · FABP7
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| Hormone |
peptide hormone: Follistatin · Growth hormone binding protein · Insulin-like growth factor binding protein (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7) · Neurophysins (Neurophysin I, II)
steroid hormone: Sex hormone binding globulin/Androgen binding protein · Transcortin · Thyroxine-binding globulin · Transthyretin
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| Metal/element |
calcium (Calcium-binding protein, Calmodulin-binding proteins) · copper (Ceruloplasmin) · iron (Iron-binding proteins, Transferrin receptor)
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| Vitamin |
Retinol binding protein (1, 2, 3, 4) · Transcobalamin
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| Other |
Acyl carrier protein · Adaptor protein · Cholesterylester transfer protein · F-box protein · GTP-binding protein · Latent TGF-beta binding protein · Light-harvesting complex · Major urinary proteins · Membrane transport protein · Odorant binding protein
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B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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Proteins: Globular proteins
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| Serum globulins |
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Alpha globulins
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serpins: alpha-1 (Alpha 1-antichymotrypsin, Alpha 1-antitrypsin) · alpha-2 (Alpha 2-antiplasmin) · Antithrombin (Heparin cofactor II)
carrier proteins: alpha-1 (Transcortin) · alpha-2 (Ceruloplasmin) · Retinol binding protein
other: alpha-1 (Orosomucoid) · alpha-2 (alpha-2-Macroglobulin, Haptoglobin)
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Beta globulins
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carrier proteins: Sex hormone-binding globulin · Transferrin
other: Angiostatin · Hemopexin · Beta-2 microglobulin · Factor H · Plasminogen · Properdin
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Gamma globulin
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Immunoglobulins
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Other
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Fibronectin (Fetal fibronectin) · Macroglobulin/Microglobulin · Transcobalamin
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| Other globulins |
Beta-lactoglobulin (Lactoferrin) · Thyroglobulin · Alpha-lactalbumin
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| Albumins |
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Egg white
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Conalbumin · Ovalbumin · Avidin
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Serum albumin
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Human serum albumin · Bovine serum albumin · Prealbumin
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Other
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C-reactive protein · Lactalbumin (Alpha-lactalbumin) · Parvalbumin · Ricin
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see also disorders of globin and globulin proteins
B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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Acute-phase proteins
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| Amyloid |
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| Other positive |
- Alpha 1-antichymotrypsin
- Alpha 1-antitrypsin
- Alpha 2-macroglobulin
- C-reactive protein
- Ceruloplasmin
- C3
- Ferritin
- Fibrin
- Haptoglobin
- Hemopexin
- Orosomucoid
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| Negative |
- Serum albumin
- Transferrin
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cell/phys/auag/auab/comp, igrc
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Metabolism: Metal metabolism
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| Transition metal |
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Iron metabolism
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Absorption in
Duodenum
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Iron(II) oxide: DMT1 (SLC11A2) · Ferritin · Hephaestin/Ferroportin (SLC11A3/SLC40A1) · Transferrin to Transferrin receptor (TFRC, TFR2)
Iron(III) oxide: Duodenal cytochrome B · Integrin · Calreticulin/mobilferrin · Ferritin
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Other
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Hepcidin/HAMP · Hemojuvelin · Iron-responsive element binding protein (Aconitase) · Ceruloplasmin · HFE · Hemosiderin · Lactoferrin
Iron-binding proteins: Ferritin
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Copper metabolism
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ATP7A · ATP7B · Ceruloplasmin · SLC31A1 · ATOX1
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Zinc metabolism
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TMC6 · TMC8 · SLC30A1 · SLC39A4
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| Electrolyte |
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Sodium metabolism
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Na⁺/K⁺-ATPase
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Phosphate metabolism
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Phosphoric acids and phosphates
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Magnesium metabolism
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Magnesium transporter
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Calcium metabolism
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Calcium-sensing receptor · Calcium-binding protein
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noco, nuvi, sysi/epon, met
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