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Information on EC 5.3.3.12 - L-dopachrome isomerase
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EC Tree
5.3.3.12 L-dopachrome isomeraseIUBMB Comments
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).
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Word Map
- 5.3.3.12
- tyrosinase
- melanin
- melanoma
-
tyrosinase-related
- melanocyte
-
melanogenesis
-
melanogenic
-
microphthalmia-associated
- melanosomes
- hyperpigmentation
- protein-2
-
anti-melanogenic
-
whitening
-
melanogenesis-related
- microphthalmia
-
pigmentary
-
dhica
-
melanoma-associated
-
amelanotic
- trp1
-
melanoblast
-
skin-whitening
-
melanocyte-specific
- 5,6-dihydroxyindole
-
depigment
-
pheomelanin
- vitiligo
-
depigmentation
-
5,6-dihydroxyindole-2-carboxylic
-
crest-derived
-
chemokine-like
-
tautomerization
-
melanin-producing
-
cloudman
-
premelanosome
- arbutin
- medicine
- drug development
- pmel17
- alpha-msh
-
alpha-melanocyte
-
anti-melanogenesis
-
mart-1
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
trp-2, dopachrome tautomerase, d-dopachrome tautomerase, macrophage inhibitory factor, macrophage migration-inhibitory factor, dopachrome conversion factor, tyrosine-related protein 2, dopachrome oxidoreductase, dopachrome-rearranging enzyme, brown (b) locus protein, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
brown (b) locus protein
-
-
-
-
D-dopachrome isomerase
D-dopachrome tautomerase
D-DT
DCF
-
-
-
-
DCT
DDT
dopachrome conversion factor
-
-
-
-
dopachrome delta-isomerase
dopachrome DELTA7-DELTA2-isomerase
-
-
-
-
dopachrome oxidoreductase
-
-
-
-
dopachrome tautomerase
dopachrome-rearranging enzyme
-
-
-
-
isomerase, dopachrome DELTA-
-
-
-
-
L-dopachchrome-methyl ester tautomerase
-
-
-
-
macrophage inhibitory factor
Macrophage migration inhibitory factor
-
-
MIF
SLATY locus protein
-
-
-
-
TRP2
-
-
-
-
tyrosine-related protein 2
-
-
-
-
DCT
-
-
-
-
dopachrome delta-isomerase
-
-
-
-
dopachrome tautomerase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-dopachrome = 5,6-dihydroxyindole-2-carboxylate
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
intramolecular oxidoreduction
-
-
-
-
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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).
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CAS REGISTRY NUMBER
COMMENTARY
130122-81-5
-
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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
L-3,4-dihydroxyphenylalanine methyl ester
methyl 3-(3,4-dioxocyclohexa-1,5-dien-1-yl)-L-alaninate
L-alpha-methyldopachrome
5,6-dihydroxy-2-methyl-2,3-dihydro-1H-indole-2-carboxylic acid
-
-
-
-
?
L-dopachrome
5,6-dihydroxyindole-2-carboxylic acid
-
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
-
-
?
dopachrome
5,6-dihydroxyindole-2-carboxylate
-
highly stereospecific for L-dopachrome
-
?
dopachrome
5,6-dihydroxyindole-2-carboxylate
-
highly stereospecific for L-dopachrome
-
?
L-3,4-dihydroxyphenylalanine methyl ester
methyl 3-(3,4-dioxocyclohexa-1,5-dien-1-yl)-L-alaninate
-
i.e. L-3,4-dihydroxyphenylalanine methyl ester hydrochloride, the catalytic residue is N-terminal Pro1
-
-
r
L-3,4-dihydroxyphenylalanine methyl ester
methyl 3-(3,4-dioxocyclohexa-1,5-dien-1-yl)-L-alaninate
-
the catalytic residue is N-terminal Pro1
-
-
r
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
-
Dct isomerizes the intermediate dopachrome to 5,6-dihydroxyindole-2-carboxylic acid, DHICA, and influences the proportion of DHICA monomer incorporated into the 5,6-dihydroxyindole, DHI, polymer in eumelanin
DHICA monomers are required to incorporate into the DHI polymer backbone of eumelanin. DHICA exhibits a potent hydroxyl radical-scavenging activity when bound to melanin, while DHI-melanin does not
-
?
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
-
Dct isomerizes the intermediate dopachrome to 5,6-dihydroxyindole-2-carboxylic acid, DHICA, and influences the proportion of DHICA monomer incorporated into the 5,6-dihydroxyindole, DHI, polymer in eumelanin
DHICA monomers are required to incorporate into the DHI polymer backbone of eumelanin. DHICA exhibits a potent hydroxyl radical-scavenging activity when bound to melanin, while DHI-melanin does not
-
?
additional information
?
-
-
existence of a common mechanism underlying radio- and chemoresistance, which is mediated by the enzyme
-
-
?
additional information
?
-
-
role of enzyme in cytoprotection by preventing the production of atoxic melanin precursor, 5,6-dihydroxyindole
-
-
?
additional information
?
-
-
isoforms of enzyme may play a part in the normal pathway of melamin biosynthesis
-
-
?
additional information
?
-
-
WM35-wild-type and WM35-C2 cells, containing overexpressed TRP-2 enzyme are incubated with various H2O2 concentrations to determine the survival rate. TRP-2 reduces oxidative stress-induced toxicity of WM35-C2 cells compared to the wild-type cells, at 300 microM H2O2 30% decrease of cell sensitivity. TRP-2 protects genomic DNA from oxidative stress damage: in wild-type WM35 cells the damaging effect on DNA is visible at 50 microM H2O2. WM35 cells containing the overexpressed TRP-2 show DNA damage after treatment with 100 microM H2O2. The overexpression of TRP-2 in HEK-293 cells shows no improvement of the cell sensitivity to oxidative stress
-
-
?
additional information
?
-
-
MIF is a 12 kDa protein with an enzymatic keto-enol tautomerase activityMIF is a homotrimeric multifunctional proinflammatory cytokine. Binding of MIF to its receptor, CD74, overview
-
-
?
additional information
?
-
-
MIF is a homotrimeric multifunctional proinflammatory cytokine. Binding of MIF to its receptor, CD74, overview
-
-
?
additional information
?
-
-
the MIF protein is multifunctional, exhibiting besides its L-dopachrome tautomerase activity, e.g. also phenylpyruvate tautomerase activity, EC 5.3.2.1, and thioredoxin-like function, or its cytokine function, overview
-
-
?
additional information
?
-
-
no substrate: L-dopachrome methyl ester, dopaminochrome, adrenochrome
-
-
?
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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
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
-
Dct isomerizes the intermediate dopachrome to 5,6-dihydroxyindole-2-carboxylic acid, DHICA, and influences the proportion of DHICA monomer incorporated into the 5,6-dihydroxyindole, DHI, polymer in eumelanin
DHICA monomers are required to incorporate into the DHI polymer backbone of eumelanin. DHICA exhibits a potent hydroxyl radical-scavenging activity when bound to melanin, while DHI-melanin does not
-
?
L-dopachrome
5,6-dihydroxyindole-2-carboxylate
-
Dct isomerizes the intermediate dopachrome to 5,6-dihydroxyindole-2-carboxylic acid, DHICA, and influences the proportion of DHICA monomer incorporated into the 5,6-dihydroxyindole, DHI, polymer in eumelanin
DHICA monomers are required to incorporate into the DHI polymer backbone of eumelanin. DHICA exhibits a potent hydroxyl radical-scavenging activity when bound to melanin, while DHI-melanin does not
-
?
additional information
?
-
-
existence of a common mechanism underlying radio- and chemoresistance, which is mediated by the enzyme
-
-
?
additional information
?
-
-
role of enzyme in cytoprotection by preventing the production of atoxic melanin precursor, 5,6-dihydroxyindole
-
-
?
additional information
?
-
-
isoforms of enzyme may play a part in the normal pathway of melamin biosynthesis
-
-
?
additional information
?
-
-
MIF is a 12 kDa protein with an enzymatic keto-enol tautomerase activityMIF is a homotrimeric multifunctional proinflammatory cytokine. Binding of MIF to its receptor, CD74, overview
-
-
?
additional information
?
-
-
MIF is a homotrimeric multifunctional proinflammatory cytokine. Binding of MIF to its receptor, CD74, overview
-
-
?
additional information
?
-
-
the MIF protein is multifunctional, exhibiting besides its L-dopachrome tautomerase activity, e.g. also phenylpyruvate tautomerase activity, EC 5.3.2.1, and thioredoxin-like function, or its cytokine function, overview
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Iron
Zinc
additional information
additional information
-
metal-containing enzyme, possibly with iron at its catalytic center
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-oxo-4-phenyl-3-butynoate
-
a potent site-directed irreversible inhibitor of the phenyl pyruvate tautomerase activity
3,6-dihydroxy-1-methyl-5-oxo-3,5-dihydro-2H-indolium
-
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
-
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
-
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
-
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
Benzyl isothiocyanate
-
specific inhibition of MIF tautomerase activity is mediated by selective modification of the N-terminal proline
Isothiocyanate
-
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
methyl 6-hydroxy-2-methyl-5-oxo-3,5-dihydro-2H-indole-2-carboxylate
-
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
additional information
-
design and synthesis of irreversible isothiocyanate-based inhibitors of MIF, inhibitory potencies and inhibition mechanism, overview
-
additional information
-
there exist several classes of inhibitors that are active against MIF tautomerase activity, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-ascorbic acid
-
enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
L-cysteine
-
enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
N-acetyl-L-cysteine
-
enzyme activity depends on the presence of a reducing compound to a final concentration of 0.1mM
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.8
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.8 - 8.2
-
pH 4.8: about 40% of maximum activity, pH 8.2: about 55% of maximum activity
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
peripheral blood mononuclear cells, expression in wild-type but no enzyme expression in vitiligo patients, overview
brenda
-
blocking endogenous enzyme by RNAi decreases proliferation of embryoic cortical neural progenitor cells
brenda
-
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
brenda
-
enzyme is expressed in all layers of the dorsal telencephalon in E10.5
brenda
-
at E15.5 and E17.5, enzyme expression is primarily localized to the ventricular zone
brenda
-
measuring of the spatial and temporal pattern of enzyme expression in vivo during neocortical neurogenesis. Enzyme is expressed in all layers of the dorsal telencephalon in E10.5. At E15.5 and E17.5, expression is primarily localized to the ventricular zone. Blocking endogenous enzyme by RNAi decreases proliferation of embryoic cortical neural progenitor cells. In adult brain, strong expression is observed in rostral migratory stream and septum. 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
brenda
-
preparation of single-cell suspensions of the tail skin
-
brenda
-
levels of DCT are elevated in melanoma cell lines that are especially resistant to chemotherapy and radiation
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
preferentially associated to, but also found in microsomal and cytosolic fractions
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
Dct inactivation elevates the level of ROS, increases the numbers of sunburn cells and apoptotic cells, and decreases the amount of eumelanin in the epidermis upon exposure to chronic UVA radiation
malfunction
-
MIF expression contributes to cell proliferation, invasiveness and neo-angiogenesis of neuroblastoma, gastric, hepatocellular, bladder, and breast carcinomas. MIF takes part in the pathogenesis of Alzheimer's disease and multiple sklerosis
malfunction
-
MIF is implicated in the pathogenesis of several inflammatory and autoimmune diseases
malfunction
-
Dct inactivation in knockout mice exposed to UVA radiation elevates the level of reactive oxygen species, increases the number of sunburn cells and apoptotic cells and decreases the amount of eumelanin in the epidermis
malfunction
a tautomerase-null protein shows reduced binding affinity to the receptors CD74 and CXCR2, and an impaired ability to induce ERK1/2 MAP kinase activation. Cells expressing the tautomerase-null protein show reduced proliferative capacity, and enzyme-deficient mice show a reduced development in benzo[a]pyrene-induced skin tumors.
malfunction
-
enzyme knockdown inhibits ERK1/2 and AKT phosphorylation, increases p53 expression and attenuates proliferation and invasion of PANC-1 cells
malfunction
-
Dct inactivation elevates the level of ROS, increases the numbers of sunburn cells and apoptotic cells, and decreases the amount of eumelanin in the epidermis upon exposure to chronic UVA radiation
-
physiological function
-
Dct is a critical enzyme in the melanogenesis pathway. It is involved in regulation of DHICA-mediated antioxidation and protection of the skin against UVA radiation
physiological function
-
DCT plays a critical role in lowering the oxidative stress resulting from melanogenesis
physiological function
increase in D-dopachrome tautomerase is a response to liver damage, accelerates melanin biosynthesis and protects the liver from oxidative stress induced by CCl4, overview
physiological function
-
MIF is an upstream regulator of innate immunity and a potential molecular link between inflammation and cancer, functional role of the MIF tautomerase activity in vivo, overview. MIF's intrinsic tautomerase activity is dispensable for this cytokine's growth-regulatory properties and support a role for the N-terminal region in protein-protein interactions
physiological function
-
MIF is involved in diverse biological processes, e.g. MIF glucocorticoid overriding activity, endotoxin lipopolysaccharide-induced TNF production, MIF-mediated stimulation of ERK1/2 MAP kinase and proliferation of serum-starved cells, MIF-mediated upregulation of arachidonic acid in macrophages, and Cox-2 activation
physiological function
-
MIF plays an essential role in both, innate and adaptive immune response. It is implicated in tumor growth and angiogenesis, an exerts an antagonistic effect against glucocorticoid immunosuppressive action, and shows glucorticoid overriding activity
physiological function
-
the enzyme is produced by NS0 cells as a factor to support proliferation, it is probably involved in autocrine regulation of proliferation, mechanism, overview
physiological function
-
Dct plays a role in the regulation of eumelanin antioxidant properties
physiological function
-
mRNA expression matrix-metalloproteinase (MMP)-1 and MMP-3 are induced by the enzyme in SGB preadipocyte cell line
physiological function
-
serum enzyme levels are elevated in patients with obesity and type 2 diabetes. and mRNA levels of MIF in subcutaneous abdominal adipose cells are positively associated with adipocyte size and insulin resistance
physiological function
-
the enzyme binds to the type II transmembrane protein, CD74, leading to its intracellular phosphorylation, the recruitment of the coreceptor CD44, and the activation of SRC family kinases and the ERK1/2 MAPK pathway. The enzyme counterregulates the inhibitory effect of glucocorticoids on tissue necrosis factor production from lipopolysaccharide-stimulated macrophages
physiological function
the enzyme inhibits the migration of macrophages. The enzyme activates the MAP kinase cascade, modulates cell migration, and counter-acts the immunosuppressive effects of glucocorticoids. For many cell types, the enzyme also acts as an important survival or anti-apoptotic factor. the enzyme is essential for the production of pro-inflammatory mediators such as tissue necrosis factor alpha, interleukin-1beta, prostaglandin E2 and nitric oxide by macrophages. The enzyme is necessary for maximal c-jun-N-terminal kinase-dependent AP-1 transactivation and subsequent CXCL8 and VEGF transcription in human lung adenocarcinoma cells
physiological function
-
the enzyme promotes tumor cell and endothelial cell migration
physiological function
-
the enzyme is beneficial in wound repair of inflamed adipose tissue by improving fibroblast survival and proliferation
physiological function
-
Dct is a critical enzyme in the melanogenesis pathway. It is involved in regulation of DHICA-mediated antioxidation and protection of the skin against UVA radiation
-
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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). TYRP2_BOVIN
517
1
58787
Swiss-Prot
Secretory Pathway (Reliability: 3)
TYRP2_CHICK
521
1
59314
Swiss-Prot
Secretory Pathway (Reliability: 5)
TYRP2_HUMAN
519
1
59145
Swiss-Prot
Secretory Pathway (Reliability: 1)
TYRP2_MOUSE
517
1
58510
Swiss-Prot
Secretory Pathway (Reliability: 3)
TYRP2_PIG
519
1
58573
Swiss-Prot
Secretory Pathway (Reliability: 3)
YELF2_DROME
452
0
51029
Swiss-Prot
Secretory Pathway (Reliability: 1)
YELF_DROME
429
0
49108
Swiss-Prot
Secretory Pathway (Reliability: 1)
MIFH_BRUMA
115
0
12320
Swiss-Prot
other Location (Reliability: 2)
MIFH_TRIMR
19
0
2058
Swiss-Prot
other Location (Reliability: 1)
MIFH_TRISP
114
0
12337
Swiss-Prot
other Location (Reliability: 2)
MIFH_TRITR
114
0
12043
Swiss-Prot
other Location (Reliability: 1)
MIFH_WUCBA
115
0
12364
Swiss-Prot
other Location (Reliability: 1)
MIF_BOVIN
115
0
12343
Swiss-Prot
other Location (Reliability: 2)
MIF_CHICK
115
0
12484
Swiss-Prot
other Location (Reliability: 1)
MIF_HUMAN
115
0
12476
Swiss-Prot
other Location (Reliability: 2)
MIF_MACFA
115
0
12476
Swiss-Prot
other Location (Reliability: 2)
MIF_MACMU
115
0
12476
Swiss-Prot
other Location (Reliability: 2)
MIF_MERUN
115
0
12449
Swiss-Prot
other Location (Reliability: 2)
MIF_MOUSE
115
0
12504
Swiss-Prot
other Location (Reliability: 2)
MIF_PIG
115
0
12451
Swiss-Prot
other Location (Reliability: 3)
MIF_RAT
115
0
12477
Swiss-Prot
other Location (Reliability: 2)
MIF_SHEEP
115
0
12343
Swiss-Prot
other Location (Reliability: 2)
MIF_XENLA
115
0
12500
Swiss-Prot
other Location (Reliability: 2)
MIF_XENTR
115
0
12524
Swiss-Prot
other Location (Reliability: 2)
A0A8B6FJF9_MYTGA
648
0
74433
TrEMBL
other Location (Reliability: 2)
G4SZ39_META2
Methylotuvimicrobium alcaliphilum (strain DSM 19304 / NCIMB 14124 / VKM B-2133 / 20Z)
115
0
12607
TrEMBL
-
A0A023B961_GRENI
115
0
11944
TrEMBL
other Location (Reliability: 1)
A1L1Y0_DANRE
513
1
58153
TrEMBL
Secretory Pathway (Reliability: 1)
D2ECG6_TELCI
115
0
12327
TrEMBL
other Location (Reliability: 2)
Q28HM0_XENTR
518
1
58250
TrEMBL
Secretory Pathway (Reliability: 2)
A0A0B4KHA3_DROME
418
0
47757
TrEMBL
Secretory Pathway (Reliability: 1)
W6M9Z9_9GAMM
115
0
12292
TrEMBL
-
A0A0B4KGZ1_DROME
413
0
47352
TrEMBL
Secretory Pathway (Reliability: 1)
B3VKX3_SHEEP
517
1
58772
TrEMBL
Secretory Pathway (Reliability: 3)
O75767_HUMAN
237
0
27324
TrEMBL
Secretory Pathway (Reliability: 1)
DOPD_RAT
118
0
13133
Swiss-Prot
Chloroplast (Reliability: 1)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
trimer
trimer
-
the tertiary structure is stabilized by hydrogen bonds and a hydrophobic core, three beta-sheets and six alpha-helices surround a traversing channel with dominant positive charge in the middle of the trimer, structure, overview. The enzyme contains a Cys-Xaa-Xaa-Cys motif required for oxido-reductase activity and MIF-like activities like glucorticoid overriding and cell proliferation
trimer
-
trimer formation is required for MIF tautomerase activity, trimer three-dimensional structure and tautomerase active site structure. The subunit interface is not as hydrophobic as the interior of the monomer, however, there is a hydrophobic patch on the surface involving residues Y36, Y95, W108, and F113, MALDI-TOF and analytical gel filtration analysis, overview
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
glycoprotein
-
Analysis of DCT tryptic peptides by MALDI-TOF/TOF determines N-glycosylation as a primary post-translational modification
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
-
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
additional information
-
modification of Pro1, e.g. via isothiocyanate inhibitors, alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability, overview
additional information
-
preparation of biotin-isothiocyanate-labeled enzyme, proteomic screening in recombinant HeLa cells and identification of the modification site by mass spectrometry
additional information
-
enzyme knockout mutant, animals are viable and do not show any abnormalities in skin, retinal pigment epithelium, or brain. Animals show a diluted coat colour phenotype due to reduced melanin content in hair. Primary melanocytes from knockout animals are viable in culture and show a normal distribution of tyrosinase and tyrosinase-related protein 1
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzymne from Sf9 insect cells by ammonium sulfate fractionation, hydroxyapatite and anion exchange chromatography, and gel filtration
-
recombinant MIF from Escherichia coli strain BL21(DE3) by anion exchange chromatography and gel filtration
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination of the tyrosinase-related protein2/DOPAchrome tautomerase gene, polymorphism analysis, overview
-
expression of the truncated enzyme lacking its carboxy-terminal transmembrane region in Spodoptera frugiperda Sf9 insect cell using a viral transfer vector
-
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
-
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
enzyme protein levels and mRNA expression are significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds
-
MIF expression is upregulated by cytokines, TNF-alpha and interleukin-I, and by bacterial endotoxins, such as lipopolysaccharides, and exotoxins
-
the enzyme is induced by low levels of glucocorticoids in vitro and in vivo
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
-
the tautomerase activity of MIF is a target for inhibitor development, overview
medicine
medicine
-
levels of enzyme correlate with relative levels of radioresistance and resistance to UV(B) treatment
medicine
-
use of enzyme as an early differentiation marker for melanoblasts and retinal pigment epithelium
medicine
-
DCT is processed as a melanoma antigen and is a potential target for immunotherapy
medicine
-
lower enzyme levels on postnatal day 6 are associated with an increased risk of developing bronchopulmonary dysplasia and late-onset neonatal sepsis
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Pawelek, J.M.
Dopachrome conversion factor functions as an isomerase
Biochem. Biophys. Res. Commun.
166
1328-1333
1990
Mus musculus
brenda
Aroca, P.; Garcia-Borron, J.C.; Solano, F.; Lozano, J.A.
Regulation of mammalian melanogenesis I: partial purification and characterization of a dopachrome converting factor: dopachrome tautomerase
Biochim. Biophys. Acta
1035
266-275
1990
Mus musculus
brenda
Winder, A.J.; Wittbjer, A.; Odh, G.; Rosengren, E.; Rorsman, H.
The mouse brown (b) locus protein functions as a dopachrome tautomerase
Pigment Cell Res.
7
305-310
1994
Mus musculus
brenda
Solano, F.; Martinez-Liarte, J.H.; Jimenez-Cervantes, C.; Garcia-Borron, J.C.; Lozano, J.A.
Dopachrome tautomerase is a zinc-containing enzyme
Biochem. Biophys. Res. Commun.
204
1243-1250
1994
Mus musculus
brenda
Palumbo, A.; d'Ischia, M.; Misuraca, G.; De Martino, L.; Prota, G.
A new dopachrome-rearranging enzyme from the ejected ink of the cuttlefish Sepia officinalis
Biochem. J.
299
839-844
1994
Sepia officinalis
brenda
Chakraborty, A.K.; Orlow, S.J.; Pawelek, J.M.
Evidence that dopachrome tautomerase is a ferrous iron-binding glycoprotein
FEBS Lett.
302
126-128
1992
Mus musculus
brenda
Tsukamoto, K.; Jackson, I.J.; Urabe, K.; Montague, P.M.; Hearing, V.J.
A second tyrosine-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase
EMBO J.
11
519-526
1992
Mus musculus
brenda
Palumbo, A.; Solano, F.; Misuraca, G.; Aroca, P.; Borron, J.C.G.; Lozano, J.A.; Prota, G.
Comparative action of dopachrome tautomerase and metal ions on the rearragement of dopachrome
Biochim. Biophys. Acta
1115
1-5
1991
Mus musculus
brenda
Solano, F.; Jimenez-Cervantes, C.; Martinez-Liarte, J.H.; Garcia-Borron, J.C.; Jara, J.R.; Lozano, J.A.
Molecular mechanism for catalysis by a new zinc-enzyme, dopachrome tautomerase
Biochem. J.
313
447-453
1996
Mus musculus
brenda
Udono, T.; Takahashi, K.; Yasumoto, K.; Yoshizawa, M.; Takeda, K.; Abe, T.; Tamai, M.; Shibahara, S.
Expression of tyrosinase-related protein 2/DOPAchrome tautomerase in the retinoblastoma
Exp. Eye Res.
72
225-234
2001
Homo sapiens
brenda
Pisarra, P.; Lupetti, R.; Palumbo, A.; Napolitano, A.; Prota, G.; Parmiani, G.; Anichini, A.; Sensi, M.
Human melanocytes and melanomas express novel mRNA isoforms of the tyrosinase-related protein-2/DOPAchrome tautomerase gene: molecular and functional characterization
J. Invest. Dermatol.
115
48-56
2000
Homo sapiens
brenda
Rosengren, E.; Rorsman, H.
Reducing compounds initiate the TRP2-catalyzed conversion of L-dopachrome to DHICA
Melanoma Res.
8
469-470
1998
Mus musculus
brenda
Suzuki, H.; Takahashi, K.; Yasumoto, K.I.; Amae, S.; Yoshizawa, M.; Fuse, N.; Shibahara, S.
Role of neurofibromin in modulation of expression of the tyrosinase-related protein 2 gene
J. Biochem.
124
992-998
1998
Homo sapiens
brenda
Furumura, M.; Solano, F.; Matsunaga, N.; Sakai, C.; Spritz, R.A.; Hearing, V.J.
Metal ligand-binding specificities of the tyrosinase-related proteins
Biochem. Biophys. Res. Commun.
242
579-585
1998
Mus musculus
brenda
Pennock, J.L.; Behnke, J.M.; Bickle, Q.D.; Devaney, E.; Grencis, R.K.; Isaac, R.E.; Joshua, G.W.; Selkirk, M.E.; Zhang, Y.; Meyer, D.J.
Rapid purification and characterization of L-dopachrome-methyl ester tautomerase (macrophage-migration-inhibitory factor) from Trichinella spiralis, Trichuris muris and Brugia pahangi
Biochem. J.
335
495-498
1998
Brugia pahangi, Homo sapiens, no activity in Caenorhabditis elegans, no activity in Heligmosomoides polygyrus, no activity in Hymenolepis diminuta, no activity in Nippostrongylus brasiliensis, no activity in Schistosoma haematobium, no activity in Schistosoma japonicum, no activity in Schistosoma mansoni, Trichinella spiralis, Trichuris muris
brenda
Pak, B.J.; Lee, J.; Thai, B.L.; Fuchs, S.Y.; Shaked, Y.; Ronai, Z.; Kerbel, R.S.; Ben-David, Y.
Radiation resistance of human melanoma analysed by retroviral insertional mutagenesis reveals a possible role for dopachrome tautomerase
Oncogene
23
30-38
2004
Homo sapiens
brenda
Costin, G.E.; Valencia, J.C.; Wakamatsu, K.; Ito, S.; Solano, F.; Milac, A.L.; Vieira, W.D.; Yamaguchi, Y.; Rouzaud, F.; et al.
Mutations in dopachrome tautomerase (Dct) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein
Biochem. J.
391
249-259
2005
Mus musculus
brenda
Guyonneau, L.; Murisier, F.; Rossier, A.; Moulin, A.; Beermann, F.
Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice
Mol. Cell. Biol.
24
3396-3403
2004
Mus musculus
brenda
Jiao, Z.; Zhang, Z.G.; Hornyak, T.J.; Hozeska, A.; Zhang, R.L.; Wang, Y.; Wang, L.; Roberts, C.; Strickland, F.M.; Chopp, M.
Dopachrome tautomerase (Dct) regulates neural progenitor cell proliferation
Dev. Biol.
296
396-408
2006
Mus musculus
brenda
Michard, Q.; Commo, S.; Belaidi, J.P.; Alleaume, A.M.; Michelet, J.F.; Daronnat, E.; Eilstein, J.; Duche, D.; Marrot, L.; Bernard, B.A.
TRP-2 specifically decreases WM35 cell sensitivity to oxidative stress
Free Radic. Biol. Med.
44
1023-1031
2008
Homo sapiens
brenda
Hiyoshi, M.; Konishi, H.; Uemura, H.; Matsuzaki, H.; Tsukamoto, H.; Sugimoto, R.; Takeda, H.; Dakeshita, S.; Kitayama, A.; Takami, H.; Sawachika, F.; Kido, H.; Arisawa, K.
D-Dopachrome tautomerase is a candidate for key proteins to protect the rat liver damaged by carbon tetrachloride
Toxicology
255
6-14
2009
Rattus norvegicus (P80254)
brenda
Cross, J.V.; Rady, J.M.; Foss, F.W.; Lyons, C.E.; Macdonald, T.L.; Templeton, D.J.
Nutrient isothiocyanates covalently modify and inhibit the inflammatory cytokine macrophage migration inhibitory factor (MIF)
Biochem. J.
423
315-321
2009
Homo sapiens
brenda
Ouertatani-Sakouhi, H.; El-Turk, F.; Fauvet, B.; Roger, T.; Le Roy, D.; Karpinar, D.P.; Leng, L.; Bucala, R.; Zweckstetter, M.; Calandra, T.; Lashuel, H.A.
A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor
Biochemistry
48
9858-9870
2009
Homo sapiens
brenda
Garai, J.; Lorand, T.
Macrophage migration inhibitory factor (MIF) tautomerase inhibitors as potential novel anti-inflammatory agents: current developments
Curr. Med. Chem.
16
1091-1114
2009
Homo sapiens
brenda
Jiang, S.; Liu, X.M.; Dai, X.; Zhou, Q.; Lei, T.C.; Beermann, F.; Wakamatsu, K.; Xu, S.Z.
Regulation of DHICA-mediated antioxidation by dopachrome tautomerase: implication for skin photoprotection against UVA radiation
Free Radic. Biol. Med.
48
1144-1151
2010
Mus musculus, Mus musculus C57BL/6
brenda
Deng, W.; Tan, Y.; Wang, X.; Xi, D.; He, Y.; Yang, S.; Mao, H.; Gao, S.
Molecular cloning, sequence characteristics, and polymorphism analyses of the tyrosinase-related protein 2 /DOPAchrome tautomerase gene of black-boned sheep (Ovis aries)
Genome
52
1001-1011
2009
Ovis aries
brenda
Spens, E.; Haeggstroem, L.
Proliferation of NS0 cells in protein-free medium: the role of cell-derived proteins, known growth factors and cellular receptors
J. Biotechnol.
141
123-129
2009
Mus musculus
brenda
Fingerle-Rowson, G.; Kaleswarapu, D.R.; Schlander, C.; Kabgani, N.; Brocks, T.; Reinart, N.; Busch, R.; Schuetz, A.; Lue, H.; Du, X.; Liu, A.; Xiong, H.; Chen, Y.; Nemajerova, A.; Hallek, M.; Bernhagen, J.; Leng, L.; Bucala, R.
A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation
Mol. Cell. Biol.
29
1922-1932
2009
Mus musculus
brenda
Vavricka, C.J.; Ray, K.W.; Christensen, B.M.; Li, J.
Purification and N-glycosylation analysis of melanoma antigen dopachrome tautomerase
Protein J.
29
204-212
2010
Homo sapiens
brenda
Bam, M.; Bagchi, T.
Absence of tyrosinase-related protein-2/dopachrome tautomerase transcripts in PBMCs from vitiligo patients
Scand. J. Immunol.
69
366-373
2009
Homo sapiens
brenda
Panzella, L.; Napolitano, A.; Dischia, M.
Is DHICA the key to dopachrome tautomerase and melanocyte functions?
Pigment Cell Melanoma Res.
24
248-249
2011
Mus musculus
brenda
Merk, M.; Mitchell, R.A.; Endres, S.; Bucala, R.
D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family
Cytokine
59
10-17
2012
Homo sapiens (P14174), Homo sapiens
brenda
Ishimoto, K.; Iwata, T.; Taniguchi, H.; Mizusawa, N.; Tanaka, E.; Yoshimoto, K.
D-dopachrome tautomerase promotes IL-6 expression and inhibits adipogenesis in preadipocytes
Cytokine
60
772-777
2012
Homo sapiens
brenda
Pasupuleti, V.; Du, W.; Gupta, Y.; Yeh, I.J.; Montano, M.; Magi-Galuzzi, C.; Welford, S.M.
Dysregulated D-dopachrome tautomerase, a hypoxia-inducible factor-dependent gene, cooperates with macrophage migration inhibitory factor in renal tumorigenesis
J. Biol. Chem.
289
3713-3723
2014
Homo sapiens
brenda
Honigman, J.S.; DiGregorio, K.M.; Dedkov, E.I.; Leheste, J.R.; Leng, L.; Bucala, R.; Torres, G.
Distribution maps of D-dopachrome tautomerase in the mouse brain
Neuroscience
226
382-387
2012
Mus musculus
brenda
Iwata, T.; Taniguchi, H.; Kuwajima, M.; Taniguchi, T.; Okuda, Y.; Sukeno, A.; Ishimoto, K.; Mizusawa, N.; Yoshimoto, K.
The action of D-dopachrome tautomerase as an adipokine in adipocyte lipid metabolism
PLoS ONE
7
e33402
2012
Homo sapiens
brenda
Merk, M.; Zierow, S.; Leng, L.; Das, R.; Du, X.; Schulte, W.; Fan, J.; Lue, H.; Chen, Y.; Xiong, H.; Chagnon, F.; Bernhagen, J.; Lolis, E.; Mor, G.; Lesur, O.; Bucala, R.
The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)
Proc. Natl. Acad. Sci. USA
108
E577-E585
2011
Homo sapiens
brenda
Roger, T.; Schlapbach, L.J.; Schneider, A.; Weier, M.; Wellmann, S.; Marquis, P.; Vermijlen, D.; Sweep, F.C.; Leng, L.; Bucala, R.; Calandra, T.; Giannoni, E.
Plasma levels of macrophage migration inhibitory factor and D-dopachrome tautomerase show a highly specific profile in early life
Front. Immunol.
8
26
2017
Homo sapiens
brenda
Guo, D.; Guo, J.; Yao, J.; Jiang, K.; Hu, J.; Wang, B.; Liu, H.; Lin, L.; Sun, W.; Jiang, X.
D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth
Int. J. Cancer
139
2056-2067
2016
Homo sapiens
brenda
Kim, B.S.; Tilstam, P.V.; Hwang, S.S.; Simons, D.; Schulte, W.; Leng, L.; Sauler, M.; Ganse, B.; Averdunk, L.; Kopp, R.; Stoppe, C.; Bernhagen, J.; Pallua, N.; Bucala, R.
D-dopachrome tautomerase in adipose tissue inflammation and wound repair
J. Cell. Mol. Med.
21
35-45
2017
Homo sapiens
brenda
Qi, D.; Atsina, K.; Qu, L.; Hu, X.; Wu, X.; Xu, B.; Piecychna, M.; Leng, L.; Fingerle-Rowson, G.; Zhang, J.; Bucala, R.; Young, L.H.
The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury
J. Clin. Invest.
124
3540-3550
2014
Mus musculus
brenda
Kobold, S.; Merk, M.; Hofer, L.; Peters, P.; Bucala, R.; Endres, S.
The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase is a therapeutic target in a murine melanoma model
Oncotarget
5
103-107
2014
Mus musculus
brenda
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