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Information on EC 1.13.11.24 - quercetin 2,3-dioxygenase and Organism(s) Aspergillus japonicus and UniProt Accession Q7SIC2
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1.13.11.24 quercetin 2,3-dioxygenaseIUBMB Comments
The enzyme from Aspergillus sp. is a copper protein whereas that from Bacillus subtilis contains iron. Quercetin is a flavonol (5,7,3',4'-tetrahydroxyflavonol).
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The taxonomic range for the selected organisms is: Aspergillus japonicus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
pirin, quercetinase, quercetin 2,3-dioxygenase, 2,3qd, 2,3-qd, flavonol 2,4-dioxygenase, mn-qdo, quercetin dioxygenase, quercetin 2,4-dioxygenase, vdqase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
flavonol 2,4-oxygenase
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quercetinase
quercetinase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
quercetin + O2 = 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
EPR study, mechanism, N of His112 is the axial ligand of type II copper site
quercetin + O2 = 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
study on mobility and flexibility of substrate cavity, molecular dynamics simulations
quercetin + O2 = 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
hybrid density functional theory study on mechanism, dioxygen attack on copper is energetically preferred
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quercetin + O2 = 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
possible reaction mechanisms and pathways, kinetics, detailed overview
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quercetin + O2 = 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
reaction mechanism, overview. Quantum mechanics/molecular mechanics (QM/MM) and QM-only study on the oxidative ring-cleaving reaction of quercetin catalyzed by quercetin 2,4-dioxygenase, i.e. 2,4-QD, which has a mononuclear type 2 copper center and incorporates two oxygen atoms at C2 and C4 positions of the substrate. Dioxygen is more likely to bind to a Cu2+ ion than to a substrate radical, involving the dissociation of the substrate from the copper ion. Then a Cu2+-alkylperoxo complex can be generated. Steric effects of the protein environment contribute to maintain the orientation of the substrate dissociated from the copper center. A prior rearrangement of the Cu2+-alkylperoxo complex and a subsequent hydrogen bond switching assisted by the movement of Glu73 can facilitate formation of an endoperoxide intermediate selectively. Reaction mechanism for endoperoxide formation, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
quercetin:oxygen 2,3-oxidoreductase (decyclizing)
The enzyme from Aspergillus sp. is a copper protein whereas that from Bacillus subtilis contains iron. Quercetin is a flavonol (5,7,3',4'-tetrahydroxyflavonol).
CAS REGISTRY NUMBER
COMMENTARY
9075-67-6
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
quercetin + O2
2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
the mechanism consists in four successive steps, the first one concerns addition of O2 on the C2 carbon atom, the second corresponds to the closure of the endoperoxo intermediate. In the two last steps, bonds are broken to produce the depside and carbon monoxide. Addition of dioxygen on the C2 atom (step 1) is associated to a pyramidalization at the C2 carbon atom and to a rotation of the B-ring with respect to the conjugated A-C rings. The second step is the rate limiting one and the free energy barriers characterized for the four flavonoids are very close, reaching about 24 kcal/mol. Differences in the values are not significant enough to be exploited to rationalize the nonlinear evolution of the degradation rate. Moreover, the relatively high energy value is expected to be lowered by taking into account the whole environment
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?
quercetin + O2
2-protocatechoylphloroglucinolcarboxylate + CO
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?
quercetin + O2
2-protocatechoylphloroglucinolcarboxylate + CO
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?
quercetin + O2
2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
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?
quercetin + O2
2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
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cleavages of the C2-C3 and C3-C4 bonds of quercetin (Que) catalyzed by 2,4-QDs
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?
additional information
?
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quercetin 2,3-dioxygenase is a copper-containing enzyme that catalyzes the insertion of molecular oxygen into polyphenolic flavonols
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?
additional information
?
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quercetin 2,3-dioxygenase is a copper-containing enzyme that catalyzes the insertion of molecular oxygen into polyphenolic flavonols
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?
additional information
?
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the enzyme opens up two C-C bonds of the heterocyclic ring of quercetin, a widespread plant flavonol
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?
additional information
?
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quercetin 2,3-dioxygenase activates molecular oxygen to catalyze the oxygenative ring-opening reaction of the O-heterocycle of quercetin to the corresponding depside (phenolic carboxylic acid esters) and carbon monoxide
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?
additional information
?
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a flavonolate ion (fla-, deprotonated substrate) is bound through the 3-hydroxy group to the copper(II) ion, which exhibits a distorted squarepyramidal geometry. The bound substrate is stabilized by Glu73 through a hydrogen-bonding interaction. Synthesis of a set of copper(II) complexes [CuIILn(AcO)] and their flavonolate adducts [CuIILn(fla)] with the series of carboxyl-group-containing ligands LnH, the treatment of the ligands with CuII(OAc)2xH2O gives the corresponding mononuclear copper(II) complexes [CuIILn(OAc)], dioxygenation of flavonol catalyzed by the binary complexes [CuIILn(AcO)] (multiturnover reaction), kinetics, overview
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?
additional information
?
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computational study on the dioxygenation reaction of the substrate flavonolate (fla) by a synthetic model complex and related species mimicking quercetin 2,4-dioxygenases, overview. The reaction mechanism obtained for the present biomimetic complexes is substantially different from the plausible enzymatic reaction. All model complexes favor a single electron transfer from flavonolate to dioxygen over a valence tautomerism, and a subsequent intersystem crossing and a ring-closure lead to a formation of a 1,2-dioxetane intermediate instead of undergoing a direct formation of a precursor endoperoxide. The generation of the 1,2-dioxetane intermediate is shown to be the rate-determining step and inclusion of a carboxylate co-ligand can enhance the reactivity, rendering this process barrier-free. Proposal of a pathway, which can circumvent a non-enzymatic reaction by involving conversion from the 1,2-dioxetane to the endoperoxide with lower barriers
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
quercetin + O2
2-protocatechoylphloroglucinolcarboxylate + CO
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?
quercetin + O2
2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate + CO + H+
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-
-
-
?
quercetin + O2
2-protocatechoylphloroglucinolcarboxylate + CO
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?
additional information
?
-
quercetin 2,3-dioxygenase is a copper-containing enzyme that catalyzes the insertion of molecular oxygen into polyphenolic flavonols
-
-
?
additional information
?
-
-
quercetin 2,3-dioxygenase is a copper-containing enzyme that catalyzes the insertion of molecular oxygen into polyphenolic flavonols
-
-
?
additional information
?
-
-
the enzyme opens up two C-C bonds of the heterocyclic ring of quercetin, a widespread plant flavonol
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
copper
Cu2+
required, enzyme-bound, structure, overview. Manual docking, different geometries of the copper site
Cu2+
additional information
Cu2+
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required, mononuclear copper(II) active site, binding structure, X-ray diffraction and NMR analysis, overview. Direct coordinative interaction between copper(II) ion and the carboxylate group of Glu73. Complexes modeling, overview
Cu2+
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required, the copper ion is mainly coordinated by three His residues and a water molecule in a distorted tetrahedral geometry. In a minor form, the metal is penta-coordinated by three His, a glutamate, and an aquo ligand in a trigonal bipyramidal geometry. The major role of the activesite metal ion could be to correctly position the substrate and to stabilize transition states and intermediates rather than to mediate electron transfer
Cu2+
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required, a flavonolate ion (fla-, deprotonated substrate) is bound through the 3-hydroxy group to the copper(II) ion, which exhibits a distorted squarepyramidal geometry
Cu2+
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the enzyme has a mononuclear type 2 copper center, steric effects of the protein environment contribute to maintain the orientation of the substrate dissociated from the copper center. A prior rearrangement of the Cu2+-alkylperoxo complex and a subsequent hydrogen bond switching assisted by the movement of Glu73 can facilitate formation of an endoperoxide intermediate selectively
additional information
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fungal quercetinases appear to exclusively utilize a Cu2+ ion for catalysis
additional information
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synthesis of a set of copper(II) complexes [CuIILn(AcO)] and their flavonolate adducts [CuIILn(fla)] with the series of carboxyl-group-containing ligands LnH, the treatment of the ligands with CuII(OAc)2xH2O gives the corresponding mononuclear copper(II) complexes [CuIILn(OAc)], ligand structures, mass spectrometric analysis, overview
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(4-{bis[1-methyl-2-(propan-2-yl)-1H-imidazol-4-yl]methyl}-1-methyl-1H-imidazol-2-yl)-2-methylpropanoic acid
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2-{4-[hydroxy(di-1H-imidazol-4-yl)methyl]-1H-imidazol-2-yl}-2-methylpropanoic acid
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chloro[(4-phenoxy-1,4,7-triazonan-1-yl-kappa3N1,N4,N7)acetato-kappaO]copper
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[3-(hydroxy-kappaO)-2-phenyl-4H-chromen-4-onato-kappaO4][bis(triphenylphosphane)]copper
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{N,N-bis[(1-methyl-1H-imidazol-4-yl-kappaN3)methyl]glycinato-kappa2N,O}(dichloro)ferrate(1-)
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
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kinetics of enzyme-substrate complexes of the active site of MII-containing quercetin 2,3-dioxygenase, overview
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
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the ring-cleaving dioxygenase belongs to the cupin superfamily, characterized by a six-stranded beta-barrel fold and conserved amino acid motifs that provide the 3His or 2- or 3His-1Glu ligand environment of a divalent metal ion. The cupin domain comprises two conserved amino acid motifs with the consensus sequences G(X)5HXH(X)3-4E(X)6G (motif 1) and G(X)5-7PXG(X)2H(X)3N
malfunction
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the mutational removal of Glu73 causes a loss of enzyme activity
additional information
additional information
Manual docking of the substrate quercetin into the active site showed that the different geometries of the copper site might be of catalytic importance
additional information
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Manual docking of the substrate quercetin into the active site showed that the different geometries of the copper site might be of catalytic importance
additional information
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synthesis of a series of flavonolate complexes as structural and functional models for the enzyme-substrate complexes of the active site of MII-containing quercetin 2,3-dioxygenase, structure analysis, overview
additional information
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synthetic routes to tris(imidazolyl)carboxylate ligands, {N,N-bis[(1-methyl-1H-imidazol-4-yl-kappaN3)methyl]glycinato-kappa2N,O}(dichloro)ferrate(1-), [3-(hydroxy-kappaO)-2-phenyl-4H-chromen-4-onato-kappaO4][bis(triphenylphosphane)]copper, (1Z,3Z)-N,N'-di(pyridin-2-yl)-1H-isoindole-1,3(2H)-diimine, chloro[(4-phenoxy-1,4,7-triazonan-1-yl-kappa3N1,N4,N7)acetato-kappaO]copper,2-{4-[hydroxy(di-1H-imidazol-4-yl)methyl]-1H-imidazol-2-yl}-2-methylpropanoic acid, and 2-(4-{bis[1-methyl-2-(propan-2-yl)-1H-imidazol-4-yl]methyl}-1-methyl-1H-imidazol-2-yl)-2-methylpropanoic acid, and representative metal complexes, which provide more accurate active site models for several classes of redox metalloenzymes, complex structures, detailed overview
additional information
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for bacterial 2,4-QDs in which Co2+ or Ni2+ is employed as a cofactor, direct electron transfer from the activated Que to dioxygen (path C) may occur in analogy with cofactor-free dioxygenases. The subsequent radical coupling via intersystem crossing leads to an ESO2 complex, because Co2+ and Ni2+ are expected to be redox-inactive in this process
additional information
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residue Glu73 plays an important role in the catalytic reaction
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). QDOI_ASPJA
350
0
37935
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
he enzyme forms homodimers, which are stabilized by an N-linked heptasaccharide at the dimer interface. The mononuclear type 2 copper center displays two distinct geometries: a distorted tetrahedral coordination, formed by His66, His68, His112, and a water molecule, and a distorted trigonal bipyramidal environment, which additionally comprises Glu73. Manual docking of the substrate quercetin into the active site showed that the different geometries of the copper site might be of catalytic importance
homodimer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
copper-containing quercetin 2,3-dioxygenase, X-ray diffraction structure determination and analysis at 1.6 A resolution
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Steiner, R.A.; Kooter, I.M.; Dijkstra, B.W.
Functional analysis of the copper-dependent quercetin 2,3-dioxygenase. 1. Ligand-induced coordination changes probed by X-ray crystallography: inhibition, ordering effect, and mechanistic insights
Biochemistry
41
7955-7962
2002
Aspergillus japonicus (Q7SIC2), Aspergillus japonicus
Kooter, I.M.; Steiner, R.A.; Dijkstra, B.W.; van Noort, P.I.; Egmond, M.R.; Huber, M.
EPR characterization of the mononuclear Cu-containing Aspergillus japonicus quercetin 2,3-dioxygenase reveals dramatic changes upon anaerobic binding of substrates
Eur. J. Biochem.
269
2971-2979
2002
Aspergillus japonicus
Steiner, R.A.; Meyer-Klaucke, W.; Dijkstra, B.W.
Functional analysis of the copper-dependent quercetin 2,3-dioxygenase. 2. X-ray absorption studies of native enzyme and anaerobic complexes with the substrates quercetin and myricetin
Biochemistry
41
7963-7968
2002
Aspergillus japonicus (Q7SIC2), Aspergillus japonicus
Fittipaldi, M.; Steiner, R.A.; Matsushita, M.; Dijkstra, B.W.; Groenen, E.J.; Huber, M.
Single-crystal EPR study at 95 GHz of the type 2 copper site of the inhibitor-bound quercetin 2,3-dioxygenase
Biophys. J.
85
4047-4054
2003
Aspergillus japonicus (Q7SIC2), Aspergillus japonicus
Siegbahn, P.E.
Hybrid DFT study of the mechanism of quercetin 2,3-dioxygenase
Inorg. Chem.
43
5944-5953
2004
Aspergillus japonicus
van den Bosch, M.; Swart, M.; van Gunsteren, W.F.; Canters, G.W.
Simulation of the substrate cavity dynamics of quercetinase
J. Mol. Biol.
344
725-738
2004
Aspergillus japonicus (Q7SIC2)
Fiorucci, S.; Golebiowski, J.; Cabrol-Bass, D.; Antonczak, S.
Molecular simulations bring new insights into flavonoid/quercetinase interaction modes
Proteins
67
961-970
2007
Aspergillus japonicus (Q7SIC2)
Fetzner, S.
Ring-cleaving dioxygenases with a cupin fold
Appl. Environ. Microbiol.
78
2505-2514
2012
Aspergillus japonicus, Bacillus subtilis, Penicillium olsonii, Streptomyces sp., Streptomyces sp. FLA / DSM 41951
Sun, Y.J.; Huang, Q.Q.; Tano, T.; Itoh, S.
Flavonolate complexes of M(II) (M = Mn, Fe, Co, Ni, Cu, and Zn). Structural and functional models for the ES (enzyme-substrate) complex of quercetin 2,3-dioxygenase
Inorg. Chem.
52
10936-10948
2013
Aspergillus japonicus
Fusetti, F., Schrter, K.H.; Steiner, R.A.; van Noort, P.I.; Pijning, T.; Rozeboom, H.J.; Kalk, K.H.; Egmond, M.R.; Dijkstra, B.W.
Crystal structure of the copper-containing quercetin 2,3-dioxygenase from Aspergillus japonicus
Structure
2
259-268
2002
Aspergillus japonicus (Q7SIC2), Aspergillus japonicus
Volkman, J.; Nicholas, K.
A synthetic quest for tris(imidazolyl) carboxylates and their metal complexes: active site models for quercetin 2,3-dioxygenases and other non-heme redox metalloenzymes
Tetrahedron
68
3368-3376
2012
Aspergillus japonicus
-
Sun, Y.; Li, P.; Huang, Q.; Zhang, J.; Itoh, S.
Dioxygenation of flavonol catalyzed by copper(II) complexes supported by carboxylate-containing ligands structural and functional models of quercetin 2,4-dioxygenase
Eur. J. Inorg. Chem.
2017
1845-1854
2017
Aspergillus japonicus
-
Saito, T.; Kawakami, T.; Yamanaka, S.; Okumura, M.
Computational study of catalytic reaction of quercetin 2,4-dioxygenase
J. Phys. Chem. B
119
6952-6962
2015
Aspergillus japonicus
Numata, T.; Saito, T.; Kawakami, T.; Yamanaka, S.; Okumura, M.
Quantum mechanics study on synthetic model of copper-containing quercetin 2,4-dioxygenase
Polyhedron
136
45-51
2016
Aspergillus japonicus
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