Information on EC 5.3.3.12 - L-dopachrome isomerase

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The expected taxonomic range for this enzyme is: Bilateria

EC NUMBER
COMMENTARY hide
5.3.3.12
-
RECOMMENDED NAME
GeneOntology No.
L-dopachrome isomerase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
L-dopachrome = 5,6-dihydroxyindole-2-carboxylate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
intramolecular oxidoreduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
eumelanin biosynthesis
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-
Metabolic pathways
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Tyrosine metabolism
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-
SYSTEMATIC NAME
IUBMB Comments
L-dopachrome keto-enol isomerase
A zinc enzyme. Stereospecific for L-dopachrome. Dopachrome methyl ester is a substrate, but dopaminochrome (2,3-dihydroindole-5,6-quinone) is not (see also EC 4.1.1.84, D-dopachrome decarboxylase).
CAS REGISTRY NUMBER
COMMENTARY hide
130122-81-5
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
adult
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
C57BL/6 mice
-
-
Manually annotated by BRENDA team
no activity in Caenorhabditis elegans
-
-
-
Manually annotated by BRENDA team
no activity in Heligmosomoides polygyrus
-
-
-
Manually annotated by BRENDA team
no activity in Hymenolepis diminuta
-
-
-
Manually annotated by BRENDA team
no activity in Nippostrongylus brasiliensis
-
-
-
Manually annotated by BRENDA team
no activity in Schistosoma haematobium
-
-
-
Manually annotated by BRENDA team
no activity in Schistosoma japonicum
-
-
-
Manually annotated by BRENDA team
no activity in Schistosoma mansoni
-
-
-
Manually annotated by BRENDA team
black-boned sheep
-
-
Manually annotated by BRENDA team
male Wistar rats
SwissProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
adult
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4-hydoxyphenylpyruvate
?
show the reaction diagram
-
-
-
-
?
D-dopachrome
?
show the reaction diagram
-
-
-
-
?
dopachrome
5,6-dihydroxyindole-2-carboxylate
show the reaction diagram
dopachrome
?
show the reaction diagram
-
melanin biosynthesis
-
-
?
L-3,4-dihydroxyphenylalanine methyl ester
methyl 3-(3,4-dioxocyclohexa-1,5-dien-1-yl)-L-alaninate
show the reaction diagram
L-alpha-methyldopachrome
5,6-dihydroxy-2-methyl-2,3-dihydro-1H-indole-2-carboxylic acid
show the reaction diagram
-
-
-
-
-
L-dopachrome
5,6-dihydroindole-2-carboxylic acid
show the reaction diagram
-
i.e. 2-carboxy-2,3-dihydroindole-5,6-quinone, the enzyme is strictly specific for the L-enantiomer. The N-terminal Pro is crucial for tautomerase activity
-
-
?
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
show the reaction diagram
L-dopachrome methyl ester
?
show the reaction diagram
-
-
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
dopachrome
?
show the reaction diagram
-
melanin biosynthesis
-
-
?
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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-
2,2'-dipyridyl
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2,3-Dihydroxybenzoic acid
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2-oxo-4-phenyl-3-butynoate
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a potent site-directed irreversible inhibitor of the phenyl pyruvate tautomerase activity
2-piperidinoethyl isothiocyanate
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-
3,6-dihydroxy-1-methyl-5-oxo-3,5-dihydro-2H-indolium
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a dopachrome derivative, 98% inhibition at 0.5 mM, mechanism of action, overview
3,6-dihydroxy-2-methyl-2,3-dihydro-5H-indol-5-one
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a dopachrome derivative, 92% inhibition at 0.5 mM, mechanism of action, overview
3,6-dihydroxy-5-oxo-3,5-dihydro-2H-indole-2-carboxylic acid
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a dopachrome derivative, complete inhibition at 0.5 mM, mechanism of action, overview
6-hydroxy-2-methyl-5-oxo-3,5-dihydro-2H-indole-2-carboxylic acid
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a dopachrome derivative, 35% inhibition at 0.5 mM, mechanism of action, overview; a dopachrome derivative, L-derivative, 29% inhibition at 0.5 mM, mechanism of action, overview
allyl isothiocyamate
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Benzyl isothiocyanate
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specific inhibition of MIF tautomerase activity is mediated by selective modification of the N-terminal proline
EDTA
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Zn2+ restores activity
ethyl isothiocyanate
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haematin
indole
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Isothiocyanate
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inhibits tautomerase activity of MIF. Modification and inhibition of MIF is not involved in the induction of phase 2 gene expression in response to isothiocyanate treatment
L-mimosine
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methallyl isothiocyanate
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methyl 6-hydroxy-2-methyl-5-oxo-3,5-dihydro-2H-indole-2-carboxylate
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a dopachrome derivative, 34% inhibition at 0.5 mM, mechanism of action, overview; a dopachrome derivative, 45% inhibition at 0.5 mM, mechanism of action, overview
phenethylisothiocyanate
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inhibits tautomerase activity of MIF
sulforaphane
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inhibits tautomerase activity of MIF
tropolone
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tryptophan
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-
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
L-ascorbic acid
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enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
L-cysteine
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enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
N-acetyl-L-cysteine
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enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
additional information
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no stimulation by D-dopachrome
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1 - 1
dopachrome
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2
tryptophan
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-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0031
2-piperidinoethyl isothiocyanate
Homo sapiens
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0.0037
allyl isothiocyamate
Homo sapiens
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0.0008
Benzyl isothiocyanate
Homo sapiens
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0.0111
ethyl isothiocyanate
Homo sapiens
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0.0014
methallyl isothiocyanate
Homo sapiens
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0.005 - 0.006
phenethylisothiocyanate
Homo sapiens
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0.001 - 0.002
sulforaphane
Homo sapiens
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-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.8 - 8.2
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pH 4.8: about 40% of maximum activity, pH 8.2: about 55% of maximum activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
ejected
Manually annotated by BRENDA team
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stage 4
Manually annotated by BRENDA team
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peripheral blood mononuclear cells, expression in wild-type but no enzyme expression in vitiligo patients, overview
Manually annotated by BRENDA team
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blocking endogenous enzyme by RNAi decreases proliferation of embryoic cortical neural progenitor cells
Manually annotated by BRENDA team
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corticotrop cells
Manually annotated by BRENDA team
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retinal pigment epithelium
Manually annotated by BRENDA team
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cell line Y79
Manually annotated by BRENDA team
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strong expression in adult
Manually annotated by BRENDA team
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strong expression in adult
Manually annotated by BRENDA team
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a human melanotic melanoma cell line
Manually annotated by BRENDA team
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overexpression of enzyme in subventricular zone cells of adult mice significantly increases the number of cells, whereas silencing Dct enzyme by RNAi decreases the cell number
Manually annotated by BRENDA team
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enzyme is expressed in all layers of the dorsal telencephalon in E10.5
Manually annotated by BRENDA team
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at E15.5 and E17.5, enzyme expression is primarily localized to the ventricular zone
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
preferentially associated to, but also found in microsomal and cytosolic fractions
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
300000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
trimer
additional information
-
structure-function relationship, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
immuno-affinity purification
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partial
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recombinant enzymne from Sf9 insect cells by ammonium sulfate fractionation, hydroxyapatite and anion exchange chromatography, and gel filtration
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recombinant MIF from Escherichia coli strain BL21(DE3) by anion exchange chromatography and gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Dct genotyping
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DNA and amino acid sequence determination of the tyrosinase-related protein2/DOPAchrome tautomerase gene, polymorphism analysis, overview
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expression in Escherichia coli strain BL21(DE3)
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expression of the truncated enzyme lacking its carboxy-terminal transmembrane region in Spodoptera frugiperda Sf9 insect cell using a viral transfer vector
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gene mif
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genotyping of healthy and autoimmune vitiligo individuals, overview
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overexpressed in WM35 melanoma cell line as model system, endogenously expressing low levels of TRP-2. TRP-2 specifically decreases WM35 cell sensitivity to oxidative stress. Overexpreesion of enzyme in HEK-293 cells has no influence on cell sensitivity to oxidative stress
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recombinant expression of MIF in HeLa cells and in Escherichia coli strain BL21(DE3)
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
carbon tetrachloride treatment of livers lead to a 12fold increased expression level of dopachrome tautomerase in male rats, proteomic analysis, overview. The increase in DDT is a response to liver damage, accelerates melanin biosynthesis and protects the liver from oxidative stress induced by CCl4
MIF expression is upregulated by cytokines, TNF-alpha and interleukin-I, and by bacterial endotoxins, such as lipopolysaccharides, and exotoxins
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the enzyme is induced by low levels of glucocorticoids in vitro and in vivo
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
P1G
inactive
G486R
-
slaty light mutation, 28fold reduction in enzyme activity, sliding of transmembrane domain towards N-terminus of protein thus interfering with the active site. Increase in pheomelanin and reduction in eumelanin produced by melanocytes in culture
P1G
-
generation of knockout mice in which the endogenous mif gene is replaced by one encoding a tautomerase-null, Pro1-Gly1 MIF protein, i.e. P1G-MIF, which is P1G-MIF is catalytically completely inactive, but maintains significant, albeit reduced, binding to its cell surface receptor CD74 and to the intracellular binding protein JAB1/CSN5. Mutant mice show a phenotype in assays of growth control and tumor induction that is intermediate between those of the wild type mif+/+ and complete MIF deficiency mif-/-, overview. Reduced development of benzo[alpha]pyrene-induced skin tumors in mif-deficient mice
R194Q
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slaty mutation, 3fold reduction in enzyme activity compared to wild-type. Increase in pheomelanin and reduction in eumelanin produced by melanocytes in culture
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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the tautomerase activity of MIF is a target for inhibitor development, overview
medicine