DB code: M00115

CATH domain 2.60.40.420 : Immunoglobulin-like Catalytic domain
2.60.40.420 : Immunoglobulin-like
2.60.40.420 : Immunoglobulin-like
2.60.40.420 : Immunoglobulin-like
2.60.40.420 : Immunoglobulin-like
2.60.40.420 : Immunoglobulin-like Catalytic domain
E.C. 1.16.3.1
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
2.60.40.420 : Immunoglobulin-like T00215 T00216 M00062 M00194

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P00450 Ceruloplasmin
EC 1.16.3.1
Ferroxidase
NP_000087.1 (Protein)
NM_000096.3 (DNA/RNA sequence)
PF00394 (Cu-oxidase)
PF07731 (Cu-oxidase_2)
PF07732 (Cu-oxidase_3)
[Graphical View]

KEGG enzyme name
ferroxidase
ceruloplasmin
ferroxidase I
iron(II): oxygen oxidoreductase
caeruloplasmin
ferro:O2 oxidoreductase
ferroxidase, iron II:oxygen oxidoreductase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P00450 CERU_HUMAN 4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O. Secreted. Binds 6 copper ions per monomer.

KEGG Pathways
Map code Pathways E.C.
MAP00860 Porphyrin and chlorophyll metabolism

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00070 C00023 C00080 C00007 C00023 C00001
E.C.
Compound Copper Fe(II) H+ O2 Fe(III) H2O
Type heavy metal heavy metal others others heavy metal H2O
ChEBI 28694
 30052
 28694
 30052
 		18248
 82664
 18248
 82664
 		15378
 15378
 		15379
 26689
 27140
 15379
 26689
 27140
 		18248
 82664
 18248
 82664
 		15377
 15377
PubChem 23978
 23978
 		23925
 23925
 		1038
 1038
 		977
 977
 		23925
 23925
 		22247451
 962
 22247451
 962
1kcwA01 Bound:_CU Unbound Unbound Unbound Unbound
1kcwA02 Bound:_CU Unbound Unbound Unbound Unbound
1kcwA03 Unbound Unbound Unbound Unbound Unbound
1kcwA04 Bound:_CU Analogue:_CU_42 Unbound Unbound Unbound
1kcwA05 Unbound Unbound Unbound Unbound Unbound
1kcwA06 Bound:3x_CU Analogue:_CU_62 Unbound Unbound Intermediate-bound:2x__O

Reference for Active-site residues
resource references E.C.
Swiss-prot;P00450 & PDB;1kcw & literature [10], [22], [25]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1kcwA01 HIS 163(Copper-2);HIS 103;HIS 161(Copper-3);HIS 101(Copper-4)
1kcwA02 HIS 276;CYS 319;HIS 324(Copper-1)
1kcwA03
1kcwA04 HIS 637;CYS 680;HIS 685;MET 690(Copper-5)
1kcwA05
1kcwA06 HIS 980;HIS 1020(Copper-2);HIS 1022(Copper-3);HIS 978;HIS 980(Copper-4);LEU 974;HIS 975;CYS 1021;HIS 1026;MET 1031(Copper-6 binding)

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[10]
[12]
[13]
[18]
Fig.6
[23]
[25]
[28]

References
[1]
Resource
Comments
Medline ID
PubMed ID 2769688
Journal J Med Chem
Year 1989
Volume 32
Pages 2158-62
Authors Elmarakby SA, Duffel MW, Rosazza JP
Title In vitro metabolic transformations of vinblastine: oxidations catalyzed by human ceruloplasmin.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 1959654
Journal FEBS Lett
Year 1991
Volume 293
Pages 164-8
Authors Andrews SC, Smith JM, Yewdall SJ, Guest JR, Harrison PM
Title Bacterioferritins and ferritins are distantly related in evolution. Conservation of ferroxidase-centre residues.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8215390
Journal Arch Biochem Biophys
Year 1993
Volume 306
Pages 111-8
Authors Musci G, Bonaccorsi di Patti MC, Calabrese L
Title The state of the copper sites in human ceruloplasmin.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8359428
Journal Biochem Soc Trans
Year 1993
Volume 21
Pages 175S
Authors Haris PI, Chowrimootoo G, Bingle C, Chapman D, Srai KS
Title Structural characterisation of human caeruloplasmin in solution by FTIR spectroscopy.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 8000877
Journal Bioorg Med Chem
Year 1994
Volume 2
Pages 543-51
Authors Anyanwutaku IO, Petroski RJ, Rosazza JP
Title Oxidative coupling of mithramycin and hydroquinone catalyzed by copper oxidases and benzoquinone. Implications for the mechanism of action of aureolic acid antibiotics.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 8307168
Journal FEBS Lett
Year 1994
Volume 338
Pages 122-6
Authors Lamb DJ, Leake DS
Title Acidic pH enables caeruloplasmin to catalyse the modification of low-density lipoprotein.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 7982945
Journal J Biol Chem
Year 1994
Volume 269
Pages 30334-9
Authors Levi S, Corsi B, Rovida E, Cozzi A, Santambrogio P, Albertini A, Arosio P
Title Construction of a ferroxidase center in human ferritin L-chain.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 8561857
Journal J Protein Chem
Year 1995
Volume 14
Pages 611-9
Authors Musci G, Bonaccorsi di Patti MC, Calabrese L
Title Modulation of the redox state of the copper sites of human ceruloplasmin by chloride.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 8696078
Journal Biometals
Year 1996
Volume 9
Pages 273-5
Authors Lovstad RA
Title On the mechanism of citrate inhibition of ceruloplasmin ferroxidase activity.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS)
Medline ID
PubMed ID
Journal J Biol Inorg Chem
Year 1996
Volume 1
Pages 15-23
Authors Zaitseva I, Zaitsev V, Card G, Moshkov K, Bax B, Ralph A, Lindley P
Title The X-ray structure of human serum ceruloplasmin at 3.1 angstrom: Nature of the copper centres
Related PDB 1kcw
Related UniProtKB P00450
[11]
Resource
Comments
Medline ID
PubMed ID 9116285
Journal Blood
Year 1997
Volume 89
Pages 2413-21
Authors Pemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EG, Kemball-Cook G
Title A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 9326646
Journal Proc Natl Acad Sci U S A
Year 1997
Volume 94
Pages 11546-51
Authors Mukhopadhyay CK, Mazumder B, Lindley PF, Fox PL
Title Identification of the prooxidant site of human ceruloplasmin: a model for oxidative damage by copper bound to protein surfaces.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 9649340
Journal Biochemistry
Year 1998
Volume 37
Pages 9570-8
Authors Machonkin TE, Zhang HH, Hedman B, Hodgson KO, Solomon EI
Title Spectroscopic and magnetic studies of human ceruloplasmin: identification of a redox-inactive reduced Type 1 copper site.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 10508415
Journal Biochemistry
Year 1999
Volume 38
Pages 12104-10
Authors Cha MK, Kim IH
Title Ceruloplasmin has a distinct active site for the catalyzing glutathione-dependent reduction of alkyl hydroperoxide.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 10460165
Journal Biochemistry
Year 1999
Volume 38
Pages 11093-102
Authors Machonkin TE, Musci G, Zhang HH, Bonaccorsi di Patti MC, Calabrese L, Hedman B, Hodgson KO, Solomon EI
Title Investigation of the anomalous spectroscopic features of the copper sites in chicken ceruloplasmin: comparison to human ceruloplasmin.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 10504390
Journal Eur J Biochem
Year 1999
Volume 265
Pages 589-97
Authors Musci G, Bellenchi GC, Calabrese L
Title The multifunctional oxidase activity of ceruloplasmin as revealed by anion binding studies.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 10473564
Journal J Biol Chem
Year 1999
Volume 274
Pages 26135-40
Authors Farver O, Bendahl L, Skov LK, Pecht I
Title Human ceruloplasmin. Intramolecular electron transfer kinetics and equilibration.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 10480920
Journal J Biol Chem
Year 1999
Volume 274
Pages 27069-75
Authors Inoue K, Akaike T, Miyamoto Y, Okamoto T, Sawa T, Otagiri M, Suzuki S, Yoshimura T, Maeda H
Title Nitrosothiol formation catalyzed by ceruloplasmin. Implication for cytoprotective mechanism in vivo.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 10550686
Journal J Biol Inorg Chem
Year 1999
Volume 4
Pages 579-87
Authors Zaitsev VN, Zaitseva I, Papiz M, Lindley PF
Title An X-ray crystallographic study of the binding sites of the azide inhibitor and organic substrates to ceruloplasmin, a multi-copper oxidase in the plasma.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 11019827
Journal Arch Biochem Biophys
Year 2000
Volume 381
Pages 119-26
Authors Van Eden ME, Aust SD
Title Intact human ceruloplasmin is required for the incorporation of iron into human ferritin.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 11165878
Journal Free Radic Biol Med
Year 2001
Volume 30
Pages 318-26
Authors Moriel P, Pereira IR, Bertolami MC, Abdalla DS
Title Is ceruloplasmin an important catalyst for S-nitrosothiol generation in hypercholesterolemia?
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11042176
Journal J Biol Chem
Year 2001
Volume 276
Pages 2678-85
Authors Bielli P, Bellenchi GC, Calabrese L
Title Site-directed mutagenesis of human ceruloplasmin:. production of a proteolytically stable protein and structure-activity relationships of type 1 sites.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 12418179
Journal Adv Protein Chem
Year 2002
Volume 60
Pages 221-69
Authors Kosman DJ
Title FET3P, ceruloplasmin, and the role of copper in iron metabolism.
Related PDB
Related UniProtKB
[24]
Resource
Comments REVIEW.
Medline ID 22049919
PubMed ID 12055353
Journal Annu Rev Nutr
Year 2002
Volume 22
Pages 439-58
Authors Hellman NE, Gitlin JD
Title Ceruloplasmin metabolism and function.
Related PDB
Related UniProtKB P00450
[25]
Resource
Comments
Medline ID
PubMed ID 12440766
Journal Cell Mol Life Sci
Year 2002
Volume 59
Pages 1413-27
Authors Bielli P, Calabrese L
Title Structure to function relationships in ceruloplasmin: a 'moonlighting' protein.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 12044861
Journal FEBS Lett
Year 2002
Volume 520
Pages 8-12
Authors Brown MA, Stenberg LM, Mauk AG
Title Identification of catalytically important amino acids in human ceruloplasmin by site-directed mutagenesis.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 12177070
Journal J Biol Chem
Year 2002
Volume 277
Pages 40823-31
Authors Vachette P, Dainese E, Vasyliev VB, Di Muro P, Beltramini M, Svergun DI, De Filippis V, Salvato B
Title A key structural role for active site type 3 copper ions in human ceruloplasmin.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 15161286
Journal J Am Chem Soc
Year 2004
Volume 126
Pages 6579-89
Authors Quintanar L, Gebhard M, Wang TP, Kosman DJ, Solomon EI
Title Ferrous binding to the multicopper oxidases Saccharomyces cerevisiae Fet3p and human ceruloplasmin: contributions to ferroxidase activity.
Related PDB
Related UniProtKB

Comments
Copper-1, 5 and 6 are bound to Cu center known as type 1 (blue copper),
copper-4 is bound to Cu center known as type 2 (non-blue copper), and
copper-2 and 3 are bound to Cu center known as type 3 (binuclear copper) (See Swiss-prot;P00450, [10] & T00215 in EzCatDB).
Copper-2, 3, and 4 form trinuclear cluster site between domain 1 and 6 (See [10] Fig. 6), while
Copper-1, 5, and 6 form mononuclear copper binding site respectively (See [10]).
The mononuclear copper binding site for Copper-6 is responsible for the reduction of substrate (see [23]). The trinuclear binding site is responsible for the 4 one-electron transfers to dioxygen that result in the formation of two water molecules (see [23]).
Thus, this enzyme catalyzes the following reactions (see [18], [25]):
(A) Oxidation of NO, giving NO(+) (one-electron oxidation)(at copper-6):
(B) Electron transfer from copper-6 to trinuclear copper:
(C) O2 reduction, producing H2O (four-electron reduction) (at trinuclear copper):
(D) Fe(II) oxidation to Fe(III):

Created Updated
2005-04-18 2009-02-26