EzCatDB: S00925
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DB codeS00925
CATH domainDomain 11.10.1280.10 : di-copper center containing domain from catechol oxidaseCatalytic domain
E.C.1.14.18.1


Enzyme Name
UniProtKBKEGG

B2ZB02Q83WS2
Protein name

Tyrosinase
Monophenol monooxygenase
Phenolase
Monophenol oxidase
Cresolase
Monophenolase
Tyrosine-dopa oxidase
Monophenol monooxidase
Monophenol dihydroxyphenylalanine:oxygen oxidoreductase
N-acetyl-6-hydroxytryptophan oxidase
Monophenol, dihydroxy-L-phenylalanine oxygen oxidoreductase
O-diphenol:O2 oxidoreductase
Phenol oxidase
SynonymsTyrosinase
Tyrosinase
PfamPF00264 (Tyrosinase)
[Graphical view]
PF00264 (Tyrosinase)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00350Tyrosine metabolism
MAP00740Riboflavin metabolism
MAP00950Isoquinoline alkaloid biosynthesis
MAP00965Betalain biosynthesis
MAP01110Biosynthesis of secondary metabolites

UniProtKB:Accession NumberB2ZB02Q83WS2
Entry nameB2ZB02_BACMEQ83WS2_9ACTO
Activity

Subunit

Subcellular location

Cofactor


Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00070C00082C00007C00355C00355C00822C00001
CompoundCopperL-tyrosineO2L-dopaL-dopadopaquinoneH2O
Typeheavy metalamino acids,aromatic ring (only carbon atom)othersamino acids,aromatic ring (only carbon atom)amino acids,aromatic ring (only carbon atom)amino acids,aromatic ring (only carbon atom)H2O
ChEBI28694
30052
17895
58315
27140
26689
15379
15765
57504
15765
57504
16852
57924
15377

PubChem23978
6942100
6057
977
6971033
6047
6971033
6047
44229226
439316
962
22247451

                
3nm8ABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3nm8BBound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3npyABound:4x_CUUnboundUnboundUnboundUnboundUnbound  
3npyBBound:4x_CUUnboundUnboundUnboundUnboundUnbound  
3nq0ABound:_CUUnboundUnboundUnboundUnboundUnbound  
3nq0BBound:_CUUnboundUnboundUnboundUnboundUnbound  
3nq1ABound:2x_CUUnboundUnboundUnboundUnboundUnbound Transition-state-analogue:KOJ
3nq1BBound:2x_CUUnboundUnboundUnboundUnboundUnbound Transition-state-analogue:KOJ
3nq5ABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3nq5BBound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3ntmABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3ntmBBound:_CUUnboundUnboundUnboundUnboundUnbound  
4d87ABound:_CUUnboundUnboundUnboundUnboundUnbound  
4d87BBound:_CUUnboundUnboundUnboundUnboundUnbound  
4hd4ABound:_CUUnboundUnboundUnboundUnboundUnbound  
4hd4BBound:_CUUnboundUnboundUnboundUnboundUnbound  
4hd6ABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
4hd6BBound:2x_CUUnboundUnboundUnboundUnboundUnbound  
4hd7ABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
4hd7BBound:2x_CUUnboundUnboundUnboundUnboundUnbound  
1wx2ABound:2x_CUUnboundAnalogue:PERUnboundUnboundUnbound  
1wx4ABound:2x_CUUnboundAnalogue:PERUnboundUnboundUnbound  
1wx5AUnboundUnboundUnboundUnboundUnboundUnbound  
1wx5CUnboundUnboundUnboundUnboundUnboundUnbound  
1wxcAUnboundUnboundUnboundUnboundUnboundUnbound  
2ahkABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
2ahlABound:2xCU1UnboundUnboundUnboundUnboundUnbound  
2zmxABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
2zmyABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
2zmzABound:2xCU1UnboundUnboundUnboundUnboundUnbound  
2zwdABound:3xCU1UnboundUnboundUnboundUnboundUnbound  
2zweABound:3x_CUUnboundUnboundUnboundAnalogue:DAH(chain B)Unbound  
2zwfABound:3x_CUUnboundUnboundUnboundAnalogue:DAH(chain B)Unbound  
2zwgABound:3x_CUUnboundUnboundUnboundAnalogue:DAH(chain B)Unbound  
3awsABound:_CUUnboundUnboundUnboundUnboundUnbound  
3awtABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3awuABound:3x_CUUnboundUnboundUnboundUnboundUnbound  
3awvABound:2x_CUUnboundUnboundUnboundUnboundUnbound  
3awwABound:3x_CUUnboundUnboundUnboundUnboundUnbound  
3awxABound:3x_CUUnboundUnboundUnboundUnboundUnbound  
3awyABound:3x_CUUnboundUnboundUnboundUnboundUnbound  
3awzABound:_CUUnboundUnboundUnboundUnboundUnbound  
3ax0ABound:2x_CUUnboundUnboundUnboundUnboundUnbound  

Active-site residues
resource
literature [14], [22], [25]
pdbCofactor-binding residuescomment
          
3nm8AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form?
3nm8BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form?
3npyAHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form
3npyBHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form
3nq0AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
 
3nq0BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
 
3nq1AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form
3nq1BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form
3nq5AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant R209H, Deoxy reduced form
3nq5BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant R209H, Deoxy reduced form
3ntmAHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
Met I form
3ntmBHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
 
4d87AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
 
4d87BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
 
4hd4AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218F
4hd4BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218F
4hd6AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218F, Met I form?
4hd6BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218F, Met I form
4hd7AHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218G, Met I form
4hd7BHIS 42;HIS 60;HIS 69(Copper-1 binding);HIS 204;HIS 208;HIS 231(Copper-2 binding)
mutant V218G, Met I form?
1wx2AHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Oxy oxidized form
1wx4AHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Oxy oxidized form
1wx5AHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
 
1wx5CHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
 
1wxcAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
 
2ahkAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form
2ahlAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Deoxy reduced form
2zmxAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form
2zmyAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form
2zmzAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Deoxy reduced form
2zwdAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Deoxy reduced form?
2zweAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form
2zwfAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form
2zwgAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form
3awsAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
 
3awtAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form
3awuAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form
3awvAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form
3awwAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form?
3awxAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form?
3awyAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met II form?
3awzAHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
 
3ax0AHIS 38;HIS 54;HIS 63(Copper-1 binding);HIS 190;HIS 194;HIS 216(Copper-2 binding)
Met I form

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[14]Fig. 9, p.8989
[15]Scheme 2, p.4550
[20]Fig. 2, p.754-756
[22]Fig. 17, p.124-127
[23]Scheme 2, p.73-74
[25]p.232-234

references
[1]
PubMed ID2846043
JournalBiochemistry
Year1988
Volume27
Pages5610-5
AuthorsHuber M, Lerch K
TitleIdentification of two histidines as copper ligands in Streptomyces glaucescens tyrosinase.
[2]
PubMed ID3130643
JournalProg Clin Biol Res
Year1988
Volume256
Pages85-98
AuthorsLerch K
TitleProtein and active-site structure of tyrosinase.
[3]
PubMed ID1348173
JournalBiochem J
Year1992
Volume282
Pages915-8
AuthorsJackman MP, Huber M, Hajnal A, Lerch K
TitleStabilization of the oxy form of tyrosinase by a single conservative amino acid substitution.
[4]
PubMed ID7873577
JournalBiochim Biophys Acta
Year1995
Volume1247
Pages1-11
AuthorsSanchez-Ferrer A, Rodriguez-Lopez JN, Garcia-Canovas F, Garcia-Carmona F
TitleTyrosinase: a comprehensive review of its mechanism.
[5]
PubMed ID9668113
JournalJ Biol Chem
Year1998
Volume273
Pages19243-50
AuthorsTsai TY, Lee YH
TitleRoles of copper ligands in the activation and secretion of Streptomyces tyrosinase.
[6]
PubMed ID9929004
JournalFEBS Lett
Year1999
Volume442
Pages215-20
AuthorsBubacco L, Salgado J, Tepper AW, Vijgenboom E, Canters GW
Title1H NMR spectroscopy of the binuclear Cu(II) active site of Streptomyces antibioticus tyrosinase.
[7]
PubMed ID10838090
JournalFEBS Lett
Year2000
Volume474
Pages228-32
Authorsvan Gastel M, Bubacco L, Groenen EJ, Vijgenboom E, Canters GW
TitleEPR study of the dinuclear active copper site of tyrosinase from Streptomyces antibioticus.
[8]
PubMed ID12235154
JournalJ Biol Chem
Year2002
Volume277
Pages44606-12
AuthorsBattaini G, Monzani E, Casella L, Lonardi E, Tepper AW, Canters GW, Bubacco L
TitleTyrosinase-catalyzed oxidation of fluorophenols.
[9]
PubMed ID12048185
JournalJ Biol Chem
Year2002
Volume277
Pages30436-44
AuthorsTepper AW, Bubacco L, Canters GW
TitleStructural basis and mechanism of the inhibition of the type-3 copper protein tyrosinase from Streptomyces antibioticus by halide ions.
[10]
PubMed ID12028580
JournalPigment Cell Res
Year2002
Volume15
Pages162-73
AuthorsGarcia-Borron JC, Solano F
TitleMolecular anatomy of tyrosinase and its related proteins: beyond the histidine-bound metal catalytic center.
[11]
PubMed ID12473668
JournalJ Biol Chem
Year2003
Volume278
Pages7381-9
AuthorsBubacco L, Van Gastel M, Groenen EJ, Vijgenboom E, Canters GW
TitleSpectroscopic characterization of the electronic changes in the active site of Streptomyces antibioticus tyrosinase upon binding of transition state analogue inhibitors.
[12]
PubMed ID15643881
JournalJ Am Chem Soc
Year2005
Volume127
Pages567-75
AuthorsTepper AW, Bubacco L, Canters GW
TitleInteraction between the type-3 copper protein tyrosinase and the substrate analogue p-nitrophenol studied by NMR.
[13]
PubMed ID16927257
JournalChemistry
Year2006
Volume12
Pages7668-75
AuthorsTepper AW, Bubacco L, Canters GW
TitleParamagnetic properties of the halide-bound derivatives of oxidised tyrosinase investigated by 1H NMR spectroscopy.
[14]
CommentsX-RAY CRYSTALLOGRAPHY (1.20 ANGSTROMS) IN COMPLEX WITH COPPER.
PubMed ID16436386
JournalJ Biol Chem
Year2006
Volume281
Pages8981-90
AuthorsMatoba Y, Kumagai T, Yamamoto A, Yoshitsu H, Sugiyama M
TitleCrystallographic evidence that the dinuclear copper center of tyrosinase is flexible during catalysis.
Related PDB1wx2,1wx4,1wx5,1wxc,2ahk,2ahl,2zmx
Related UniProtKBQ83WS2
[15]
PubMed ID16795103
JournalAngew Chem Int Ed Engl
Year2006
Volume45
Pages4546-50
AuthorsDecker H, Schweikardt T, Tuczek F
TitleThe first crystal structure of tyrosinase: all questions answered?
[16]
PubMed ID16403014
JournalFEBS J
Year2006
Volume273
Pages257-70
AuthorsHernandez-Romero D, Sanchez-Amat A, Solano F
TitleA tyrosinase with an abnormally high tyrosine hydroxylase/dopa oxidase ratio.
[17]
PubMed ID17698026
JournalArch Biochem Biophys
Year2007
Volume465
Pages320-7
AuthorsBubacco L, Spinazze R, della Longa S, Benfatto M
TitleX-ray absorption analysis of the active site of Streptomyces antibioticus Tyrosinase upon binding of transition state analogue inhibitors.
[18]
PubMed ID18336914
JournalJ Inorg Biochem
Year2008
Volume102
Pages1170-89
AuthorsDe A, Mandal S, Mukherjee R
TitleModeling tyrosinase activity. Effect of ligand topology on aromatic ring hydroxylation: an overview.
[19]
CommentsNUCLEOTIDE SEQUENCE.
PubMed ID19672047
JournalJ Mol Microbiol Biotechnol
Year2009
Volume17
Pages188-200
AuthorsShuster V, Fishman A
TitleIsolation, cloning and characterization of a tyrosinase with improved activity in organic solvents from Bacillus megaterium.
Related UniProtKBB2ZB02
[20]
PubMed ID19735457
JournalPigment Cell Melanoma Res
Year2009
Volume22
Pages750-60
AuthorsOlivares C, Solano F
TitleNew insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins.
[21]
PubMed ID20823537
JournalActa Crystallogr Sect F Struct Biol Cryst Commun
Year2010
Volume66
Pages1101-3
AuthorsSendovski M, Kanteev M, Shuster Ben-Yosef V, Adir N, Fishman A
TitleCrystallization and preliminary X-ray crystallographic analysis of a bacterial tyrosinase from Bacillus megaterium.
[22]
PubMed ID19690900
JournalJ Biol Inorg Chem
Year2010
Volume15
Pages117-29
AuthorsDeeth RJ, Diedrich C
TitleStructural and mechanistic insights into the oxy form of tyrosinase from molecular dynamics simulations.
[23]
PubMed ID20875779
JournalArch Biochem Biophys
Year2011
Volume505
Pages67-74
AuthorsMarino SM, Fogal S, Bisaglia M, Moro S, Scartabelli G, De Gioia L, Spada A, Monzani E, Casella L, Mammi S, Bubacco L
TitleInvestigation of Streptomyces antibioticus tyrosinase reactivity toward chlorophenols.
[24]
PubMed ID21730070
JournalJ Biol Chem
Year2011
Volume286
Pages30219-31
AuthorsMatoba Y, Bando N, Oda K, Noda M, Higashikawa F, Kumagai T, Sugiyama M
TitleA molecular mechanism for copper transportation to tyrosinase that is assisted by a metallochaperone, caddie protein.
Related PDB3aws,3awt,3awu,3awv,3aww,3awx,3awy,3awz,3ax0
[25]
CommentsX-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH COPPER AND ZINC.
PubMed ID21040728
JournalJ Mol Biol
Year2011
Volume405
Pages227-37
AuthorsSendovski M, Kanteev M, Ben-Yosef VS, Adir N, Fishman A
TitleFirst structures of an active bacterial tyrosinase reveal copper plasticity.
Related PDB3nm8,3npy,3nq0,3nq1,3nq5,3ntm
Related UniProtKBB2ZB02
[26]
PubMed ID22539021
JournalAppl Microbiol Biotechnol
Year2013
Volume97
Pages1953-61
AuthorsGoldfeder M, Egozy M, Shuster Ben-Yosef V, Adir N, Fishman A
TitleChanges in tyrosinase specificity by ionic liquids and sodium dodecyl sulfate.
Related PDB4d87
[27]
PubMed ID23305929
JournalBiochim Biophys Acta
Year2013
Volume1834
Pages629-33
AuthorsGoldfeder M, Kanteev M, Adir N, Fishman A
TitleInfluencing the monophenolase/diphenolase activity ratio in tyrosinase.
Related PDB4hd4,4hd6,4hd7

comments
This enzyme catalyzes the two distinct reactions as follows:
(1) L-tyrosine + 1/2 O2 = L-dopa (ortho hydroxylation of monophenol; monophenolase activity)
(2) L-dopa + 1/2 O2 = dopaquinone + H2O (two-electron oxidation of ortho-diphenol; diphenolase activity)
This enzyme belongs to the type-3 copper protein family, which includes hemocyanin and catechol oxidase (EC 1.10.3.1). The type-3 copper proteins contain a binuclear copper active site, which consists of two closely spaced copper atoms each coordinated by three histidine residues (see [10], [12], [14]). Catechol oxidase can catalyze only oxydation of ortho-diphenol, but lacks hydroxylation activity for monophenol.
According to the literature, the dinuclear copper active site exists in three redox forms:
(a) The deoxy (reduced) form [Cu(I)-Cu(I)];
(b) The oxy (oxidized) form [Cu(II)-O2(2-)-Cu(II)]; Molecular oxygen is bound as peroxide in a side-on bridging mode.
(c) The met (resting) form [Cu(II)-OH(-)-Cu(II)]; Cu(II) ions are bridged to either a water molecule or hydroxide ion.
The deoxy form can bind a molecular oxygen to give the oxy form.
Moreover, there is another redox form, half-met form [Cu(I)-OH(-)-Cu(II)], which is EPR active (see [12]). In this form, one of the two coppers is in the oxidized form.
According to the literature [15] and [22], the met form can be categorized into two types: met I with a single bridging ligand, and met II with two bridging ones.
Here, CuA is coordinated by His42, His60 and His69 (of 3nm8 in PDB), whereas CuB is coordinated by His His204, His208 and His231. There has been long-standing debate on whether substrate hydroxyl groups bind to CuA or CuB, particluarly for monophenolase reaction. The literature ([15], [20], [22] and [25]) supports the mechanism in which monophenol hydroxyl group is bound to CuA, whereas other reports ([12], [14] and [23]) suggest that monophenol docks to CuB.

createdupdated
2013-07-092013-07-24


Copyright: Nozomi Nagano, JST & CBRC-AIST
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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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