EzCatDB: M00194
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DB codeM00194
RLCP classification10.100012.100.10290 : Electron transfer
10.12100.110.10080 : Electron transfer
10.100110.100.10300 : Electron transfer
CATH domainDomain 11.20.210.10 : Cytochrome C Oxidase; Chain ACatalytic domain
Domain 21.20.1070.10 : Rhopdopsin 7-helix transmembrane proteins
Domain 32.60.40.420 : Immunoglobulin-likeCatalytic domain
Domain 41.-.-.-
E.C.1.9.3.1
CSA1ehk

CATH domainRelated DB codes (homologues)
1.20.210.10 : Cytochrome C Oxidase; Chain AM00062
2.60.40.420 : Immunoglobulin-likeT00215,T00216,M00115,M00062

Enzyme Name
UniProtKBKEGG

Q56408Q5SJ79P98052Q5SJ80P82543
Protein nameCytochrome c oxidase subunit 1Cytochrome c oxidase subunit 1Cytochrome c oxidase subunit 2Cytochrome c oxidase subunit 2Cytochrome c oxidase polypeptide 2Acytochrome-c oxidase
cytochrome oxidase
cytochrome a3
cytochrome aa3
Warburg's respiratory enzyme
indophenol oxidase
indophenolase
complex IV (mitochondrial electron transport)
ferrocytochrome c oxidase
NADH cytochrome c oxidase
SynonymsEC 1.9.3.1
Cytochrome c oxidase polypeptide I
Cytochrome c ba(3) subunit I
Cytochrome cba3 subunit 1
EC 1.9.3.1
Cytochrome c oxidase polypeptide I
Cytochrome c ba(3) subunit I
Cytochrome cba3 subunit 1
EC 1.9.3.1
Cytochrome c oxidase polypeptide II
Cytochrome c ba(3) subunit II
Cytochrome cba3 subunit 2
EC 1.9.3.1
Cytochrome c oxidase polypeptide II
Cytochrome c ba(3) subunit II
Cytochrome cba3 subunit 2
EC 1.9.3.1
Cytochrome c oxidase polypeptide IIA
Cytochrome c ba(3) subunit IIA
Cytochrome cba3 subunit 2A
RefSeq
YP_144401.1 (Protein)
NC_006461.1 (DNA/RNA sequence)

YP_144400.1 (Protein)
NC_006461.1 (DNA/RNA sequence)
YP_144399.1 (Protein)
NC_006461.1 (DNA/RNA sequence)
PfamPF00115 (COX1)
[Graphical view]
PF00115 (COX1)
[Graphical view]
PF00116 (COX2)
[Graphical view]
PF00116 (COX2)
PF09125 (COX2-transmemb)
[Graphical view]
PF08113 (CoxIIa)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00190Oxidative phosphorylation

UniProtKB:Accession NumberQ56408Q5SJ79P98052Q5SJ80P82543
Entry nameCOX1_THETHCOX1_THET8COX2_THETHCOX2_THET8COXA_THET8
Activity4 ferrocytochrome c + O(2) + 4 H(+) = 4 ferricytochrome c + 2 H(2)O.4 ferrocytochrome c + O(2) + 4 H(+) = 4 ferricytochrome c + 2 H(2)O.4 ferrocytochrome c + O(2) + 4 H(+) = 4 ferricytochrome c + 2 H(2)O.4 ferrocytochrome c + O(2) + 4 H(+) = 4 ferricytochrome c + 2 H(2)O.4 ferrocytochrome c + O(2) + 4 H(+) = 4 ferricytochrome c + 2 H(2)O.
Subunit




Subcellular locationCell membrane, Multi-pass membrane protein (By similarity).Cell membrane, Multi-pass membrane protein.Cell membrane, Peripheral membrane protein.Cell membrane, Single-pass membrane protein.Cell membrane, Single-pass membrane protein.
CofactorBinds 2 heme groups (By similarity).,Copper B (By similarity).Binds 2 heme groups (By similarity).,Copper B (By similarity).



Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00070C00032C00032C00126C00007C00125C00001
CompoundCopperHeme AHeme A3Ferrocytochrome cO2Ferricytochrome cH2O
Typeheavy metalaromatic ring (with nitrogen atoms),carboxyl group,heavy metalaromatic ring (with nitrogen atoms),carboxyl group,heavy metalamide group,amine group,aromatic ring (with nitrogen atoms),carboxyl group,heavy metal,sulfide groupothersamide group,amine group,aromatic ring (with nitrogen atoms),carboxyl group,heavy metal,sulfide groupH2O
ChEBI28694
30052
17627
26355
17627
26355

27140
26689
15379

15377
PubChem23978



977

962
22247451
               
1xmeABound:_CUAnalogue:HEMAnalogue:HASUnboundUnboundUnbound 
1ehkABound:_CUAnalogue:HEMAnalogue:HASUnboundUnboundUnbound 
1xmeB01UnboundUnboundUnboundUnboundUnboundUnbound 
1ehkB01UnboundUnboundUnboundUnboundUnboundUnbound 
2fwlB01UnboundUnboundUnboundUnboundUnboundUnbound 
1xmeB02Bound:CUAUnboundUnboundUnboundUnboundUnbound 
1ehkB02Bound:CUAUnboundUnboundUnboundUnboundUnbound 
2fwlB02Bound:CUAUnboundUnboundBound:HEC(chain A)UnboundUnbound 
2cuaABound:CUAUnboundUnboundUnboundUnboundUnbound 
2cuaBBound:CUAUnboundUnboundUnboundUnboundUnbound 
1xmeCUnboundUnboundUnboundUnboundUnboundUnbound 
1ehkCUnboundUnboundUnboundUnboundUnboundUnbound 

Active-site residues
pdbCatalytic residuesCofactor-binding residuesMain-chain involved in catalysis
           
1xmeAHIS 384;HIS 386
HIS 384(Heme A3 Fe1 binding);HIS 72;HIS 386(Heme A Fe2 binding);HIS 233;HIS 282;HIS 283(Cu binding)
PHE 385;ARG 449;ARG 450
1ehkAHIS 384;HIS 386
HIS 384(Heme A3 Fe1 binding);HIS 72;HIS 386(Heme A Fe2 binding);HIS 233;HIS 282;HIS 283(Cu binding)
PHE 385;ARG 449;ARG 450
1xmeB01 
 
 
1ehkB01 
 
 
2fwlB01 
 
 
1xmeB02PHE 88;HIS 157
HIS 114;CYS 149;GLN 151;CYS 153;HIS 157;MET 160(dinuclear Cu binding)
ALA 87;PHE 88
1ehkB02PHE 88;HIS 157
HIS 114;CYS 149;GLN 151;CYS 153;HIS 157;MET 160(dinuclear Cu binding)
ALA 87;PHE 88
2fwlB02PHE 88;HIS 157
HIS 114;CYS 149;GLN 151;CYS 153;HIS 157;MET 160(dinuclear Cu binding)
ALA 87;PHE 88
2cuaAPHE 88;HIS 157
HIS 114;CYS 149;GLN 151;CYS 153;HIS 157;MET 160(dinuclear Cu binding)
ALA 87;PHE 88
2cuaBPHE 88;HIS 157
HIS 114;CYS 149;GLN 151;CYS 153;HIS 157;MET 160(dinuclear Cu binding)
ALA 87;PHE 88
1xmeC 
 
 
1ehkC 
 
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[8]p.1770-1773
[11]Fig.10, p.14511-14512

references
[1]
PubMed ID7615066
JournalFEBS Lett
Year1995
Volume368
Pages132-4
AuthorsSoulimane T, Gohlke U, Huber R, Buse G
TitleThree-dimensional crystals of cytochrome-c oxidase from Thermus thermophilus diffracting to 3.8 A resolution.
[2]
PubMed ID9399580
JournalJ Biochem (Tokyo)
Year1997
Volume122
Pages764-71
AuthorsSakamoto J, Handa Y, Sone N
TitleA novel cytochrome b(o/a)3-type oxidase from Bacillus stearothermophilus catalyzes cytochrome c-551 oxidation.
[3]
PubMed ID9299406
JournalBiochem Biophys Res Commun
Year1997
Volume237
Pages572-6
AuthorsSoulimane T, von Walter M, Hof P, Than ME, Huber R, Buse G
TitleCytochrome-c552 from Thermus thermophilus: a functional and crystallographic investigation.
[4]
PubMed ID9281430
JournalJ Mol Biol
Year1997
Volume271
Pages629-44
AuthorsThan ME, Hof P, Huber R, Bourenkov GP, Bartunik HD, Buse G, Soulimane T
TitleThermus thermophilus cytochrome-c552: A new highly thermostable cytochrome-c structure obtained by MAD phasing.
[5]
PubMed ID10486572
JournalFEBS Lett
Year1999
Volume457
Pages98-102
AuthorsSiletskiy S, Soulimane T, Azarkina N, Vygodina TV, Buse G, Kaulen A, Konstantinov A
TitleTime-resolved generation of a membrane potential by ba3 cytochrome c oxidase from Thermus thermophilus. Evidence for reduction-induced opening of the binuclear center.
[6]
CommentsX-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS)
Medline ID99287095
PubMed ID10360350
JournalNat Struct Biol
Year1999
Volume6
Pages509-16
AuthorsWilliams PA, Blackburn NJ, Sanders D, Bellamy H, Stura EA, Fee JA, McRee DE
TitleThe CuA domain of Thermus thermophilus ba3-type cytochrome c oxidase at 1.6 A resolution.
Related PDB2cua
Related UniProtKBP98052
[7]
PubMed ID11152118
JournalProtein Sci
Year2000
Volume9
Pages2068-73
AuthorsSoulimane T, Than ME, Dewor M, Huber R, Buse G
TitlePrimary structure of a novel subunit in ba3-cytochrome oxidase from Thermus thermophilus.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS)
Medline ID20237613
PubMed ID10775261
JournalEMBO J
Year2000
Volume19
Pages1766-76
AuthorsSoulimane T, Buse G, Bourenkov GP, Bartunik HD, Huber R, Than ME
TitleStructure and mechanism of the aberrant ba(3)-cytochrome c oxidase from thermus thermophilus.
Related PDB1ehk
Related UniProtKBP98052,P82543
[9]
PubMed ID11716725
JournalJ Am Chem Soc
Year2001
Volume123
Pages11678-85
AuthorsFernandez CO, Cricco JA, Slutter CE, Richards JH, Gray HB, Vila AJ
TitleAxial ligand modulation of the electronic structures of binuclear copper sites: analysis of paramagnetic 1H NMR spectra of Met160Gln Cu(A).
[10]
PubMed ID15735345
JournalActa Crystallogr D Biol Crystallogr
Year2005
Volume61
Pages340-3
AuthorsHunsicker-Wang LM, Pacoma RL, Chen Y, Fee JA, Stout CD
TitleA novel cryoprotection scheme for enhancing the diffraction of crystals of recombinant cytochrome ba3 oxidase from Thermus thermophilus.
Related PDB1xme
[11]
PubMed ID16554303
JournalJ Biol Chem
Year2006
Volume281
Pages14503-13
AuthorsMuresanu L, Pristovsek P, Lohr F, Maneg O, Mukrasch MD, Ruterjans H, Ludwig B, Lucke C
TitleThe electron transfer complex between cytochrome c552 and the CuA domain of the Thermus thermophilus ba3 oxidase. A combined NMR and computational approach.
Related PDB2fwl

comments
Although this enzyme is partially homologous to that from P. denitrificans (Bacteria) (M00062 in EzCatDB), the subunit/domain compositions seem to be slightly different from the counterpart enzyme.
Bacterial enzymes are composed of 3 or 4 subunits. Subunits I and II form the functional core of the enzyme complex. The subunit I binds a copper ion (CuB), two heme groups (heme A and heme A3). The subunit II binds a binuclear copper ion pair, CuA. Heme A3 and CuB form a binuclear centre for O2 reduction.
Taken together, this enzyme catalyzes the following reactions, electron transfers and dioxygen reduction, coupling with proton pumping.
4 cyt c(red) + 8 H+(in) + O2 = 4 cyt c(ox) + 2 H2O + 4 H+(out)
This enzyme catalyzes the following reactions:
(A) Electron transfer from ba3-cytochrome c (substrate;ferrocytochrome c) to CuA (subunit II):
(B) Electron transfer from CuA (subunit II) to heme A (subunit I):
(C) Electron transfer from heme A (subunit I) to binculear center (heme A3 & CuB) (subunit I):
(D) Electron transfer from CuA (subunit II) directly to CuB (subunit I):
(E) Reduction of dioxygen (O2) to H2O (at the binuclear center):
(F) Proton pump:
According to the literature [8] and [11], the following reaction proceeds as follows:
(A) Electron transfer from cytochrome c (substrate;ferrocytochrome c) to CuA (subunit II):
(A1) Indirect transfer through mainchain atoms of Ala87 and Phe88 (subunit II) to Met160 bound to CuA-1 (see [11]).
(B) Electron transfer from CuA (subunit II) to heme A (subunit I):
(B1) Indirect transfer through His157 (subunit II), mainchain carbonyl oxygen of Arg449 and mainchain amide of Arg450 (subunit I), and propionate (carboxylate) group of heme A (see M00062).
(C) Electron transfer from heme A (subunit I) to binculear center (heme A3 & CuB) (subunit I):
(C1) Indirect transfer through His386 bound to heme A iron, mainchain of Phe385, and His384 bound to heme A3 iron (see M00062).
On the other hand, the literature [8] proposed an additional electron pathway between CuA (subunit II) and CuB (subunit I).
(D) Electron transfer from CuA (subunit II) directly to CuB (subunit I):
(D1) Indirect transfer through Gln151 bound to CuA (subunit I), via Tyr136 and Trp229, and His283 bound to CuB (subunit I) (see [8]).

createdupdated
2004-03-242009-02-26
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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