EzCatDB: M00115
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DB codeM00115
CATH domainDomain 12.60.40.420 : Immunoglobulin-likeCatalytic domain
Domain 22.60.40.420 : Immunoglobulin-like
Domain 32.60.40.420 : Immunoglobulin-like
Domain 42.60.40.420 : Immunoglobulin-like
Domain 52.60.40.420 : Immunoglobulin-like
Domain 62.60.40.420 : Immunoglobulin-likeCatalytic domain
E.C.1.16.3.1

CATH domainRelated DB codes (homologues)
2.60.40.420 : Immunoglobulin-likeT00215,T00216,M00062,M00194

Enzyme Name
UniProtKBKEGG

P00450
Protein nameCeruloplasminferroxidase
ceruloplasmin
ferroxidase I
iron(II): oxygen oxidoreductase
caeruloplasmin
ferro:O2 oxidoreductase
ferroxidase, iron II:oxygen oxidoreductase
SynonymsEC 1.16.3.1
Ferroxidase
RefSeqNP_000087.1 (Protein)
NM_000096.3 (DNA/RNA sequence)
PfamPF00394 (Cu-oxidase)
PF07731 (Cu-oxidase_2)
PF07732 (Cu-oxidase_3)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00860Porphyrin and chlorophyll metabolism

UniProtKB:Accession NumberP00450
Entry nameCERU_HUMAN
Activity4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O.
Subunit
Subcellular locationSecreted.
CofactorBinds 6 copper ions per monomer.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00070C00023C00080C00007C00023C00001
CompoundCopperFe(II)H+O2Fe(III)H2O
Typeheavy metalheavy metalothersothersheavy metalH2O
ChEBI28694
30052
18248
82664
15378
27140
26689
15379
18248
82664
15377

PubChem23978
23925
1038
977
23925
962
22247451

               
1kcwA01Bound:_CUUnbound UnboundUnbound Unbound
1kcwA02Bound:_CUUnbound UnboundUnbound Unbound
1kcwA03UnboundUnbound UnboundUnbound Unbound
1kcwA04Bound:_CUAnalogue:_CU 42 UnboundUnbound Unbound
1kcwA05UnboundUnbound UnboundUnbound Unbound
1kcwA06Bound:3x_CUAnalogue:_CU 62 UnboundUnbound Intermediate-bound:2x__O

Active-site residues
resource
Swiss-prot;P00450 & PDB;1kcw & literature [10], [22], [25]
pdbCofactor-binding residues
         
1kcwA01HIS 163(Copper-2);HIS 103;HIS 161(Copper-3);HIS 101(Copper-4)
1kcwA02HIS 276;CYS 319;HIS 324(Copper-1)
1kcwA03 
1kcwA04HIS 637;CYS 680;HIS 685;MET 690(Copper-5)
1kcwA05 
1kcwA06HIS 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
ReferencesSectionsNo. of steps in catalysis
[10]

[12]

[13]

[18]Fig.6
[23]

[25]

[28]


references
[1]
PubMed ID2769688
JournalJ Med Chem
Year1989
Volume32
Pages2158-62
AuthorsElmarakby SA, Duffel MW, Rosazza JP
TitleIn vitro metabolic transformations of vinblastine: oxidations catalyzed by human ceruloplasmin.
[2]
PubMed ID1959654
JournalFEBS Lett
Year1991
Volume293
Pages164-8
AuthorsAndrews SC, Smith JM, Yewdall SJ, Guest JR, Harrison PM
TitleBacterioferritins and ferritins are distantly related in evolution. Conservation of ferroxidase-centre residues.
[3]
PubMed ID8215390
JournalArch Biochem Biophys
Year1993
Volume306
Pages111-8
AuthorsMusci G, Bonaccorsi di Patti MC, Calabrese L
TitleThe state of the copper sites in human ceruloplasmin.
[4]
PubMed ID8359428
JournalBiochem Soc Trans
Year1993
Volume21
Pages175S
AuthorsHaris PI, Chowrimootoo G, Bingle C, Chapman D, Srai KS
TitleStructural characterisation of human caeruloplasmin in solution by FTIR spectroscopy.
[5]
PubMed ID8000877
JournalBioorg Med Chem
Year1994
Volume2
Pages543-51
AuthorsAnyanwutaku IO, Petroski RJ, Rosazza JP
TitleOxidative coupling of mithramycin and hydroquinone catalyzed by copper oxidases and benzoquinone. Implications for the mechanism of action of aureolic acid antibiotics.
[6]
PubMed ID8307168
JournalFEBS Lett
Year1994
Volume338
Pages122-6
AuthorsLamb DJ, Leake DS
TitleAcidic pH enables caeruloplasmin to catalyse the modification of low-density lipoprotein.
[7]
PubMed ID7982945
JournalJ Biol Chem
Year1994
Volume269
Pages30334-9
AuthorsLevi S, Corsi B, Rovida E, Cozzi A, Santambrogio P, Albertini A, Arosio P
TitleConstruction of a ferroxidase center in human ferritin L-chain.
[8]
PubMed ID8561857
JournalJ Protein Chem
Year1995
Volume14
Pages611-9
AuthorsMusci G, Bonaccorsi di Patti MC, Calabrese L
TitleModulation of the redox state of the copper sites of human ceruloplasmin by chloride.
[9]
PubMed ID8696078
JournalBiometals
Year1996
Volume9
Pages273-5
AuthorsLovstad RA
TitleOn the mechanism of citrate inhibition of ceruloplasmin ferroxidase activity.
[10]
CommentsX-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS)
JournalJ Biol Inorg Chem
Year1996
Volume1
Pages15-23
AuthorsZaitseva I, Zaitsev V, Card G, Moshkov K, Bax B, Ralph A, Lindley P
TitleThe X-ray structure of human serum ceruloplasmin at 3.1 angstrom: Nature of the copper centres
Related PDB1kcw
Related UniProtKBP00450
[11]
PubMed ID9116285
JournalBlood
Year1997
Volume89
Pages2413-21
AuthorsPemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EG, Kemball-Cook G
TitleA molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin.
[12]
PubMed ID9326646
JournalProc Natl Acad Sci U S A
Year1997
Volume94
Pages11546-51
AuthorsMukhopadhyay CK, Mazumder B, Lindley PF, Fox PL
TitleIdentification of the prooxidant site of human ceruloplasmin: a model for oxidative damage by copper bound to protein surfaces.
[13]
PubMed ID9649340
JournalBiochemistry
Year1998
Volume37
Pages9570-8
AuthorsMachonkin TE, Zhang HH, Hedman B, Hodgson KO, Solomon EI
TitleSpectroscopic and magnetic studies of human ceruloplasmin: identification of a redox-inactive reduced Type 1 copper site.
[14]
PubMed ID10508415
JournalBiochemistry
Year1999
Volume38
Pages12104-10
AuthorsCha MK, Kim IH
TitleCeruloplasmin has a distinct active site for the catalyzing glutathione-dependent reduction of alkyl hydroperoxide.
[15]
PubMed ID10460165
JournalBiochemistry
Year1999
Volume38
Pages11093-102
AuthorsMachonkin TE, Musci G, Zhang HH, Bonaccorsi di Patti MC, Calabrese L, Hedman B, Hodgson KO, Solomon EI
TitleInvestigation of the anomalous spectroscopic features of the copper sites in chicken ceruloplasmin: comparison to human ceruloplasmin.
[16]
PubMed ID10504390
JournalEur J Biochem
Year1999
Volume265
Pages589-97
AuthorsMusci G, Bellenchi GC, Calabrese L
TitleThe multifunctional oxidase activity of ceruloplasmin as revealed by anion binding studies.
[17]
PubMed ID10473564
JournalJ Biol Chem
Year1999
Volume274
Pages26135-40
AuthorsFarver O, Bendahl L, Skov LK, Pecht I
TitleHuman ceruloplasmin. Intramolecular electron transfer kinetics and equilibration.
[18]
PubMed ID10480920
JournalJ Biol Chem
Year1999
Volume274
Pages27069-75
AuthorsInoue K, Akaike T, Miyamoto Y, Okamoto T, Sawa T, Otagiri M, Suzuki S, Yoshimura T, Maeda H
TitleNitrosothiol formation catalyzed by ceruloplasmin. Implication for cytoprotective mechanism in vivo.
[19]
PubMed ID10550686
JournalJ Biol Inorg Chem
Year1999
Volume4
Pages579-87
AuthorsZaitsev VN, Zaitseva I, Papiz M, Lindley PF
TitleAn X-ray crystallographic study of the binding sites of the azide inhibitor and organic substrates to ceruloplasmin, a multi-copper oxidase in the plasma.
[20]
PubMed ID11019827
JournalArch Biochem Biophys
Year2000
Volume381
Pages119-26
AuthorsVan Eden ME, Aust SD
TitleIntact human ceruloplasmin is required for the incorporation of iron into human ferritin.
[21]
PubMed ID11165878
JournalFree Radic Biol Med
Year2001
Volume30
Pages318-26
AuthorsMoriel P, Pereira IR, Bertolami MC, Abdalla DS
TitleIs ceruloplasmin an important catalyst for S-nitrosothiol generation in hypercholesterolemia?
[22]
PubMed ID11042176
JournalJ Biol Chem
Year2001
Volume276
Pages2678-85
AuthorsBielli P, Bellenchi GC, Calabrese L
TitleSite-directed mutagenesis of human ceruloplasmin:. production of a proteolytically stable protein and structure-activity relationships of type 1 sites.
[23]
PubMed ID12418179
JournalAdv Protein Chem
Year2002
Volume60
Pages221-69
AuthorsKosman DJ
TitleFET3P, ceruloplasmin, and the role of copper in iron metabolism.
[24]
CommentsREVIEW.
Medline ID22049919
PubMed ID12055353
JournalAnnu Rev Nutr
Year2002
Volume22
Pages439-58
AuthorsHellman NE, Gitlin JD
TitleCeruloplasmin metabolism and function.
Related UniProtKBP00450
[25]
PubMed ID12440766
JournalCell Mol Life Sci
Year2002
Volume59
Pages1413-27
AuthorsBielli P, Calabrese L
TitleStructure to function relationships in ceruloplasmin: a 'moonlighting' protein.
[26]
PubMed ID12044861
JournalFEBS Lett
Year2002
Volume520
Pages8-12
AuthorsBrown MA, Stenberg LM, Mauk AG
TitleIdentification of catalytically important amino acids in human ceruloplasmin by site-directed mutagenesis.
[27]
PubMed ID12177070
JournalJ Biol Chem
Year2002
Volume277
Pages40823-31
AuthorsVachette P, Dainese E, Vasyliev VB, Di Muro P, Beltramini M, Svergun DI, De Filippis V, Salvato B
TitleA key structural role for active site type 3 copper ions in human ceruloplasmin.
[28]
PubMed ID15161286
JournalJ Am Chem Soc
Year2004
Volume126
Pages6579-89
AuthorsQuintanar L, Gebhard M, Wang TP, Kosman DJ, Solomon EI
TitleFerrous binding to the multicopper oxidases Saccharomyces cerevisiae Fet3p and human ceruloplasmin: contributions to ferroxidase activity.

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):

createdupdated
2005-04-182009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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