Ceruloplasmin and what it might do

  • J. Healy
  • K. Tipton
Amine oxidase structure and function


The blue coloured plasma protein ceruloplasmin binds up to 95% of circulating copper, and has several possible functions. It has been proposed to function in copper transport, oxidation of organic amines, iron(II) oxidation and the regulation of cellular iron levels, and catechols, radical scavenging and other antioxidant processes. This account will consider the relative importance of these multiple functions in terms of the physiological roles of ceruloplasmin.

Keywords: Ceruloplasmin, copper, amine oxidase, ferroxidase, iron, catechol oxidase 


  1. Armendariz, AD, Gonzalez, M, Alexander, V, Loguinov, AV, Vulpe, CD 2004Gene expression profiling in chronic copper overload reveals upregulation of Prnp and AppPhysiol Genomics204554CrossRefPubMedGoogle Scholar
  2. Berg, D, Gerlach, M, Youdim, MB, Double, KL, Zecca, L,  et al. 2002Brain iron pathways and their relevance to Parkinson’s diseaseJ Neurochem79225236CrossRefGoogle Scholar
  3. Boll, MC, Sotelo, J, Otero, E, Alcaraz-Zubeldia, M, Rios, C 1999Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson’s diseaseNeurosci Lett265155158CrossRefPubMedGoogle Scholar
  4. Burkitt, MJ 2001A critical overview of the chemistry of copper-dependent low-density lipoprotein oxidation: roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasminArch Biochem Biophys394117135CrossRefPubMedGoogle Scholar
  5. Calabrese, L, Carbonaro, M, Musci, G 1989Presence of coupled trinuclear copper cluster in mammalian ceruloplasmin is essential for efficient electron transfer to oxygenJ Biol Chem26461836187PubMedGoogle Scholar
  6. Choi, SY, Kwon, HY, Kwon, OB, Eum, WS, Kang, JH 2000Fragmentation of human ceruloplasmin induced by hydrogen peroxideBiochimie82175180CrossRefPubMedGoogle Scholar
  7. Das, SK, Ray, K 2006Wilson’s disease: an updateNat Clin Pract Neurol2482493CrossRefPubMedGoogle Scholar
  8. De Iuliis, A, Burlina, AP, Boschetto, R, Zambenedetti, P,  et al. 2002Increased dopamine peroxidation in postmortem Parkinsonian brainBiochim Biophys Acta15736367PubMedGoogle Scholar
  9. Dexter, DT, Carayon, A, Javoy-Agid, F, Agid, Y,  et al. 1991Alterations in the levels of ironA ferritin, and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal gangliaBrain11419531975CrossRefPubMedGoogle Scholar
  10. Dougherty, JJ, Hoekstra, WG 1982Effects of vitamin E and selenium on copper-induced lipid peroxidation in vivo and on acute copper toxicityProc Soc Exp Biol Med169201208PubMedGoogle Scholar
  11. Dumoulin, MJ, Chahine, R, Atanasiu, R, Nadeau, R, Mateescu, MA 2006Comparative antioxidant and cardioprotective effects of ceruloplasmin, superoxide dismutase and albuminArzneimittelforschg46855861Google Scholar
  12. Dutra, F, Ciriolo, MR, Calabrese, L, Bechara, EJ 2005Aminoacetone induces oxidative modification to human plasma ceruloplasminChem Res Toxicol18755760CrossRefPubMedGoogle Scholar
  13. Farver, O, Bendahl, L, Skov, LK, Pecht, I 1999Human ceruloplasmin. Intramolecular electron transfer kinetics and equilibrationJ Biol Chem12742613526140CrossRefGoogle Scholar
  14. Feichtenhofer, S, Fabjan, JS, Abuja, PM 2001Ceruloplasmin as low-density lipoprotein oxidase: activation by ascorbate and dehydroascorbateFEBS Lett5014246CrossRefPubMedGoogle Scholar
  15. Floris, G, Medda, R, Padiglia, A, Musci, G 2000The physiopathological significance of ceruloplasmin. A possible therapeutic approachBiochem Pharmacol6017351741CrossRefPubMedGoogle Scholar
  16. Forte, G, Bocca, B, Senofonte, O, Petrucci, F,  et al. 2004Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson’s diseaseJ Neural Transm11110311040CrossRefPubMedGoogle Scholar
  17. Fortna, RR, Watson, HA, Nyquist, SE 1999Glycosyl phosphatidylinositol-anchored ceruloplasmin is expressed by rat Sertoli cells and is concentrated in detergent-insoluble membrane fractionsBiol Reprod6110421049CrossRefPubMedGoogle Scholar
  18. Ganaraja, B, Pavithran, P, Ghosh, S 2004Effect of estrogen on plasma ceruloplasmin level in rats exposed to acute stressInd J Med Sci58150154Google Scholar
  19. Gitlin, JD 1998AceruloplasminemiaPediatr Res44271276CrossRefPubMedGoogle Scholar
  20. Goldstein, IM, Kaplan, HB, Edelson, HS 1979Ceruloplasmin. A scavenger of superoxide anion radicalsJ Biol Chem25440404045PubMedGoogle Scholar
  21. Gutteridge, JM 1985Inhibition of the Fenton reaction by the protein ceruloplasmin and other copper complexes. Assessment of feroxidase and radical scavenging activitiesChem Biol Interact56113120CrossRefPubMedGoogle Scholar
  22. Harris, ZL 2003AceruloplasminemiaJ Neurol Sci207108109CrossRefPubMedGoogle Scholar
  23. Hellman, N, Gitlin, J 2002Ceruloplasmin metabolism and functionAnnu Rev Nutr22439458CrossRefPubMedGoogle Scholar
  24. Jeong, SY, David, S 2003Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous systemJ Biol Chem2782714427148CrossRefPubMedGoogle Scholar
  25. Johnson, S 2001Is Parkinson’s disease the heterozygote form of Wilson’s disease: PD = 1/2WD?Medical hypotheses56171173CrossRefPubMedGoogle Scholar
  26. Kang, JH, Kim, KS, Choi, SY, Kwon, HY, Won, MH 2001Oxidative modification of human ceruloplasmin by peroxyl radicalsBiochim Biophys Acta15683036PubMedGoogle Scholar
  27. Kim, RH, Park, JE, Park, JW 2000Ceruloplasmin enhances DNA damage induced by hydrogen peroxide in vitroFree Radical Res338189CrossRefGoogle Scholar
  28. Kim, RH, Kwon, OJ, Park, JW 2001Ceruloplasmin enhances DNA damage induced by cysteine/iron in vitroBiochimie83487495CrossRefPubMedGoogle Scholar
  29. Klomp, LW, Gitlin, JD 1996Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemiaHum Mol Genet519891996CrossRefPubMedGoogle Scholar
  30. Klomp, LW, Farhangrazi, ZS, Dugan, LL, Gitlin, JD 1996Ceruloplasmin gene expression in the murine central nervous systemJ Clin Invest98207215CrossRefPubMedGoogle Scholar
  31. Koschinsky, ML, Funk, WD, van Oost, BA, MacGillivray, RT 1986Complete cDNA sequence of human preceruloplasminProc Natl Acad Sci USA8350865090CrossRefPubMedGoogle Scholar
  32. Loeffler, DA, LeWitt, PA, Juneau, PL, Sima, AA,  et al. 1996Increased regional brain concentrations of ceruloplasmin in neurodegenerative disordersBrain Res738265274CrossRefPubMedGoogle Scholar
  33. Lutsenko, S, Petris, MJ 2003Function and regulation of the mammalian copper-transporting ATPases: insights from biochemical and cell biological approachesJ Membr Biol191112CrossRefPubMedGoogle Scholar
  34. Meyer, LA, Durley, AP, Prohaska, JR, Harris, ZL 2001Copper transport and metabolism are normal in aceruloplasminemic miceJ Biol Chem2763685736861CrossRefPubMedGoogle Scholar
  35. Mouithys-Mickalad, A, Deby, C, Deby-Dupont, G, Lamy, M 1998An electron spin resonance (ESR) study on the mechanism of ascorbyl radical production by metal-binding proteinsBiometals118188CrossRefPubMedGoogle Scholar
  36. Mukhopadhyay, CK, Mazumder, B, Lindley, PF, Fox, PL 1997Identification of the prooxidant site of human ceruloplasmin: a model for oxidative damage by copper bound to protein surfacesProc Natl Acad Sci USA941154611551CrossRefPubMedGoogle Scholar
  37. Musci, G, Bonaccorsi di Patti, MC, Calabrese, L 1995Modulation of the redox state of the copper sites of human ceruloplasmin by chlorideJ Protein Chem14611619CrossRefPubMedGoogle Scholar
  38. Musci, G, Bellenchi, GC, Calabrese, L 1999The multifunctional oxidase activity of ceruloplasmin as revealed by anion binding studiesEur J Biochem265589597CrossRefPubMedGoogle Scholar
  39. Oide, T, Yoshida, K, Kaneko, K, Ohta, M, Arima, K 2006Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemiaNeuropathol Appl Neurobiol32170176CrossRefPubMedGoogle Scholar
  40. Osaki, S 1966Kinetic Studies of Ferrous Ion Oxidation with Crystalline Human Ferroxidase (Ceruloplasmin)J Biol Chem24150535059PubMedGoogle Scholar
  41. Osaki, S, Johnson, DA, Frieden, E 1966The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serumJ Biol Chem24127462751PubMedGoogle Scholar
  42. Padiglia, A, Medda, R, Lorrai, A, Biggio, G,  et al. 1997Modulation of 6-hydroxydopamine oxidation by various proteinsBiochem Pharmacol5310651068CrossRefPubMedGoogle Scholar
  43. Paris, I, Dagnino-Subiabre, A, Marcelain, K, Bennett, LB,  et al. 2001Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell lineJ Neurochem77519529CrossRefPubMedGoogle Scholar
  44. Park, YS, Suzuki, K, Taniguchi, N, Gutteridge, JM 1999Glutathione peroxidase-like activity of caeruloplasmin as an important lung antioxidantFEBS Lett458133136CrossRefPubMedGoogle Scholar
  45. Patel, BN, Dunn, RJ, David, S 2000Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brainJ Biol Chem27543054310CrossRefPubMedGoogle Scholar
  46. Patel, BN, Dunn, RJ, Jeong, SY, Zhu, Q,  et al. 2002Ceruloplasmin regulates iron levels in the CNS and prevents free radical injuryJ Neurosci2265786686PubMedGoogle Scholar
  47. Portnoy, ME, Rosenzweig, AC, Rae, T, Huffman, DL,  et al. 1999Structure-function analyses of the ATX1 metallochaperoneJ Biol Chem2741504115045CrossRefPubMedGoogle Scholar
  48. Prohaska, JR, Gybina, AA 2004Intracellular copper transport in mammalsJ Nutr13410031006PubMedGoogle Scholar
  49. Shukla, N, Maher, J, Masters, J, Angelini, GD, Jeremy, JY 2006Does oxidative stress change ceruloplasmin from a protective to a vasculopathic factor?Atherosclerosis187238250CrossRefPubMedGoogle Scholar
  50. Squitti, R, Pasqualetti, P, Dal Forno, G, Moffa, F,  et al. 2005Excess of serum copper not related to ceruloplasmin in Alzheimer diseaseNeurology6410401046PubMedGoogle Scholar
  51. Squitti, R, Barbati, G, Rossi, L, Ventriglia, M,  et al. 2006Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tauNeurology677682CrossRefPubMedGoogle Scholar
  52. Stoj, C, Kosman, DJ 2003Cuprous oxidase activity of yeast Fet3p and human ceruloplasmin: implication for functionFEBS Lett554422426CrossRefPubMedGoogle Scholar
  53. Swain, JA, Darley-Usmar, V, Gutteridge, JM 2004Peroxynitrite releases copper from ceruloplasmin: implications for atherosclerosisFEBS Lett3424952CrossRefGoogle Scholar
  54. Tagawa, A, Ono, S, Shibata, M, Imai, T,  et al. 2001A new neurological entity manifesting as involuntary movements and dysarthria with possible abnormal copper metabolismJ Neurol Neurosurg Psychiatr71780783CrossRefPubMedGoogle Scholar
  55. Tsiroulnikov, K, Rezaei, H, Dalgalarrondo, M, Chobert, JM,  et al. 2006Cu(II) induces small-size aggregates with amyloid characteristics in two alleles of recombinant ovine prion proteinsBiochim Biophys Acta176412181226PubMedGoogle Scholar
  56. Vassiliev, V, Harris, ZL, Zatta, P 2005Ceruloplasmin in neurodegenerative diseasesBrain Res Rev49633640CrossRefPubMedGoogle Scholar
  57. Varela-Nallar, L, Toledo, EM, Larrondo, LF, Cabral, AL,  et al. 2006Induction of cellular prion protein gene expression by copper in neuronsAm J Physiol Cell Physiol290C271C281CrossRefPubMedGoogle Scholar
  58. Young, SN, Curzon, G 1972A method for obtaining linear reciprocal plots with caeruloplasmin and its application in a study of the kinetic parameters of caeruloplasmin substratesBiochem J129273283PubMedGoogle Scholar
  59. Zaitsev, VN, Zaitseva, I, Papiz, M, Lindley, PF 1999An X-ray crystallographic study of the binding sites of the azide inhibitor and organic substrates to ceruloplasmin, a multi-copper oxidase in the plasmaJ Biol Inorg Chem4579587CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • J. Healy
    • 1
  • K. Tipton
    • 1
  1. 1.Department of BiochemistrySchool of Biochemistry and Immunology, Trinity CollegeDublinIreland

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