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Information on EC 1.13.11.11 - tryptophan 2,3-dioxygenase
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1.13.11.11 tryptophan 2,3-dioxygenaseIUBMB Comments
A protohemoprotein. In mammals, the enzyme appears to be located only in the liver. This enzyme, together with EC 1.13.11.52, indoleamine 2,3-dioxygenase, catalyses the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism . The enzyme is specific for tryptophan as substrate, but is far more active with L-tryptophan than with D-tryptophan .
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Word Map
- 1.13.11.11
- indoleamine
- kynurenine
-
immunotherapy
- heme
- serotonin
-
checkpoint
- l-trp
- n-formylkynurenine
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quinolinic
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tolerogenic
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3-monooxygenase
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3,4-dioxygenase
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heme-containing
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2,3-dioxygenase-1
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tryptophan-degrading
- 3-hydroxyanthranilate
- indoleamine-2,3-dioxygenase
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picolinic
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tryptophan-catabolizing
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pyrrolase
- 3-hydroxykynurenine
- medicine
- drug development
The enzyme appears in viruses and cellular organisms
Synonyms
tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase 1, ido-1, tryptophan-2,3-dioxygenase, indoleamine 2,3-dioxygenase 2, ido-2, tryptophan 2,3-dioxygenase 2, xctdo, l-tryptophan:oxygen 2,3-oxidoreductase (decyclizing), 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
EC 1.11.1.4
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formerly
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IDO-1
TDO
TDO2
tryptophan 2,3-dioxygenase 2
XcTDO
TDO
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-tryptophan + O2 = N-formyl-L-kynurenine
catalytic mechanism, modeling. hTDO exists as two discrete species with markedly different ligand binding properties. The active site environment of the slowly rebinding species is structurally very heterogeneous and ligand access to greatly hindered. Binding of the L-Trp substrate stabilizes the faster-binding species, which features a well-structured active site and offers facile access of the ligand to the heme iron. This mechanism ensures that the ternary complex forms mainly by first binding the L-Trp substrate, which primes the active site for the subsequent binding of O2, which ensures efficient enzyme action
L-tryptophan + O2 = N-formyl-L-kynurenine
the dioxygenation reaction is initiated by a direct attack of O2 on the C2 atom of the L-Trp indole ring, catalytic mechanism, overview. Exo binding site for L-Trp, located about 42 A from the active site and formed by residues conserved among tryptophan-auxotrophic TDOs. Trp binding at this exo site does not affect enzyme catalysis but instead it retards the degradation of hTDO through the ubiquitin-dependent proteasomal pathway
L-tryptophan + O2 = N-formyl-L-kynurenine
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SYSTEMATIC NAME
IUBMB Comments
L-tryptophan:oxygen 2,3-oxidoreductase (decyclizing)
A protohemoprotein. In mammals, the enzyme appears to be located only in the liver. This enzyme, together with EC 1.13.11.52, indoleamine 2,3-dioxygenase, catalyses the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism [5]. The enzyme is specific for tryptophan as substrate, but is far more active with L-tryptophan than with D-tryptophan [2].
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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-tryptophan + O2
3alpha-hydroxyhexahydropyrrolo[2,3-b]indole-2-carboxylic acid
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-
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?
5-fluoro-L-tryptophan + O2
5-fluoro-N-formyl-L-kynurenine
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?
5-fluoro-L-tryptophan + O2
5-fluoro-N-formyl-L-kynurenine
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-
?
L-tryptophan + O2
N-formyl-L-kynurenine
kinetic and spectroscopic characterization of the catalytic ternary complex of tryptophan 2,3-dioxygenase
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-
?
L-tryptophan + O2
N-formyl-L-kynurenine
kinetic and spectroscopic characterization of the catalytic ternary complex of tryptophan 2,3-dioxygenase
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-
?
L-tryptophan + O2
N-formyl-L-kynurenine
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?
L-tryptophan + O2
N-formyl-L-kynurenine
cleavage of the C2-C3 bond in the indole moiety of L-Trp and incorporation of one oxygen molecule
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?
L-tryptophan + O2
N-formyl-L-kynurenine
the enzyme has broad substrate specificity for various indoleamines such as L-tryptophan and serotonin. It catalyzes the oxidation of the pyrrole ring of tryptophan to form N-formylkynurenine, which is later metabolized to formic acid and kynurenine
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-
?
L-tryptophan + O2
N-formyl-L-kynurenine
the enzyme has broad substrate specificity for various indoleamines such as L-tryptophan and serotonin. It catalyzes the oxidation of the pyrrole ring of tryptophan to form N-formylkynurenine, which is later metabolized to formic acid and kynurenine
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?
L-tryptophan + O2
N-formyl-L-kynurenine
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?
L-tryptophan + O2
N-formyl-L-kynurenine
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?
additional information
?
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enzyme TDO is highly substrate-specific for L-Trp and the related derivatives 6-fluoro-Trp and 5-fluoro-Trp
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?
additional information
?
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enzyme TDO is highly substrate-specific for L-Trp and the related derivatives 6-fluoro-Trp and 5-fluoro-Trp
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?
additional information
?
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no activity with D-Trp. No evidence for the accumulation of Compound II during TDO catalysis, instead a ternary [Fe(II)-O2, L-Trp] complex is detected under steady state conditions. Absence of a Compound II species in the steady state in TDO is not due to an intrinsic inability of the TDO enzyme to form ferryl heme, because Compound II can be formed directly through a different route in which ferrous heme is reacted with peroxide
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?
additional information
?
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substrate recognition and binding structures, overview. The EG segment in hTDO plays a critical role in promoting NFK release, thereby allowing Trp binding during multiple turnover
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?
additional information
?
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substrate recognition and binding structures, overview. The EG segment in hTDO plays a critical role in promoting NFK release, thereby allowing Trp binding during multiple turnover
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?
additional information
?
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in mouse liver homogenate, TDO activity is five times lower for D-Trp than that for L-Trp. L-Trp is the preferred substrate for nicotinamide synthesis because L-Trp metabolism is more efficient than D-Trp in mice
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?
additional information
?
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the kcat of tryptophan-2,3-dioxygenase (TDO) is 10 times lower for D-Trp than that for L-Trp in vitro
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?
additional information
?
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in mouse liver homogenate, TDO activity is five times lower for D-Trp than that for L-Trp. L-Trp is the preferred substrate for nicotinamide synthesis because L-Trp metabolism is more efficient than D-Trp in mice
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?
additional information
?
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the kcat of tryptophan-2,3-dioxygenase (TDO) is 10 times lower for D-Trp than that for L-Trp in vitro
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?
additional information
?
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no activity witth D-Trp. No evidence for the accumulation of Compound II during TDO catalysis, instead a ternary [Fe(II)-O2, L-Trp] complex is detected under steady state conditions. Absence of a Compound II species in the steady state in TDO is not due to an intrinsic inability of the TDO enzyme to form ferryl heme, because Compound II can be formed directly through a different route in which ferrous heme is reacted with peroxide
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?
additional information
?
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no activity witth D-Trp. No evidence for the accumulation of Compound II during TDO catalysis, instead a ternary [Fe(II)-O2, L-Trp] complex is detected under steady state conditions. Absence of a Compound II species in the steady state in TDO is not due to an intrinsic inability of the TDO enzyme to form ferryl heme, because Compound II can be formed directly through a different route in which ferrous heme is reacted with peroxide
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?
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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-tryptophan + O2
N-formyl-L-kynurenine
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?
L-tryptophan + O2
N-formyl-L-kynurenine
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?
L-tryptophan + O2
N-formyl-L-kynurenine
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?
additional information
?
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in mouse liver homogenate, TDO activity is five times lower for D-Trp than that for L-Trp. L-Trp is the preferred substrate for nicotinamide synthesis because L-Trp metabolism is more efficient than D-Trp in mice
-
-
?
additional information
?
-
in mouse liver homogenate, TDO activity is five times lower for D-Trp than that for L-Trp. L-Trp is the preferred substrate for nicotinamide synthesis because L-Trp metabolism is more efficient than D-Trp in mice
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?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
heme
heme-containing enzyme. The heme prosthetic group is present as a heme-ferric form that must be reduced to the heme-ferrous prior to mediate L-tryptophan oxidation
heme
the enzyme is heme dependent, requiring the reduction of ferric to ferrous-iron to bind to L-tryptophan
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1R,2S)-2-([[6-(trifluoromethyl)-1H-indazol-4-yl]amino]methyl)cyclohexan-1-ol
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(1R,2S)-2-[[(6-bromo-1-methyl-1H-indazol-4-yl)amino]methyl]cyclohexan-1-ol
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(2E)-3-(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)prop-2-enoic acid
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(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)boronic acid
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1-(2-hydroxy-4-methylphenyl)-3-{2-[(propan-2-yl)oxy]phenyl}propane-1,3-dione
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1-(3-bromothiophen-2-yl)-2-(3-methyl-1,4-dihydronaphthalen-2-yl)ethan-1-one
most potent inhibitor capable of blocking both indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) activity, with the IC50 value for BT-549 cells at 0.00342 mM
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1-(3-[(4-acetyl-1-piperazinyl)carbonyl]benzyl)-1H-naphtho-[2,3-d][1,2,3]triazole-4,9-dione
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1-(3-[(4-methyl-1-piperazinyl)carbonyl]benzyl)-1H-naphtho-[2,3-d][1,2,3]triazole-4,9-dione
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1-(4-[(4-acetylpiperazin-1-yl)carbonyl]benzyl)-1H-naphtho-[2,3-d][1,2,3]triazole-4,9-dione
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1-(4-[(4-methoxypiperidin-1-yl)carbonyl]benzyl)-1Hnaphtho[2,3-d][1,2,3]triazole-4,9-dione
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1-[(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)methyl]piperidine-3-carboxylic acid
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1-[(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)methyl]piperidine-4-carboxylic acid
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1-[(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)methyl]proline
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1-[3-(4-morpholinylcarbonyl)benzyl]-1H-naphtho[2,3-d]-[1,2,3]triazole-4,9-dione
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1-[4-(morpholin-4-ylcarbonyl)benzyl]-1H-naphtho[2,3-d]-[1,2,3]triazole-4,9-dione
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1-[4-[(4-methylpiperazin-1-yl)carbonyl]benzyl]-1H-naphtho-[2,3-d][1,2,3]triazole-4,9-dione
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2-(4-[(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]-triazol-1-yl)methyl]phenyl)-N,N-diethylacetamide
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3-[(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)methyl]-N,N-diethylbenzamide
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3-[(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)methyl]benzoic acid
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4-([[(1S,2R)-2-hydroxycyclohexyl]methyl]amino)-1H-indazole-6-carboxylic acid
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4-[(1Z)-2-[(6-bromo-1H-indazol-4-yl)amino]-N-hydroxyethanimidoyl]phenol
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4-[(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)methyl]-N,N-diethylbenzamide
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4-[(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)methyl]benzoic acid
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5-(6-fluoro-1H-indol-3-yl)-1-[2-(piperazin-1-yl)ethyl]-1H-benzotriazole
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5-phenyl-1,2,3-thiadiazol-4-amine
potent tryptophan 2,3-dioxygenase 2 inhibitor with modest selectivity over indolamine 2,3-dioxygenase 1 and with improved human whole blood stability
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8-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolo[2,1-b]quinazoline-6,12-dione
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8-fluoro-2-[(1H-1,2,3-triazol-1-yl)methyl]indolo[2,1-b]quinazoline-6,12-dione
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8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-2-carbaldehyde
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ethyl (2E)-3-(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)prop-2-enoate
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methyl 1-[(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)methyl]piperidine-3-carboxylate
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methyl 1-[(8-fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-2-yl)methyl]piperidine-4-carboxylate