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Enzyme Nomenclature
Information on EC 1.14.19.9 - tryptophan 7-halogenase
Word Map on EC 1.14.19.9
- 1.14.19.9
-
regioselective
-
polyketide
- fluorescens
-
instal
-
bromination
-
chloramine
- hocl
-
regiospecific
-
dichlorination
- venezuelae
-
enediyne
- haloperoxidases
- vancomycin
- rebeccamycin
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
1.14.19.9
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RECOMMENDED NAME
GeneOntology No.
tryptophan 7-halogenase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
monooxygenase-like mechanism proposed. First, FADH2 is produced by a flavin reductase using NADH. FADH2 binds to flavin-free enzyme and reacts to enzyme-bound 4alpha-flavin hydroperoxide which attacks L-tryptophan. Activated tryptophan is attacked by chloride as a nucleophile, the resulting halohydrin is dehydrated to the end product 7-chlorotryptophan
-
tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
FADH2 and O2 form an 4alpha-FAD-OOH intermediate that decays to 4alpha-FAD-OH. Tryptophan likely does not react directly with any flavin intermediate. Substrate chlorination occurs after completion of the flavin redox reactions
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tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
proposed mechanism: after formation of a FAD-OOH intermediate, the reactive chlorine is generated as a FAD-O-Cl intermediate. Chlorination of L-tryptophan proceeds by attack of the aromatic pi electrons on the intermediate in a two-electron mechanism and abstraction of a proton generates the final product
tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
FADH2 reacts with O2 to make peroxyflavin, which is decomposed by Cl-. the resulting HOCl is guided through the tunnel to tryptophan, where it is activated to participate in electrophilic aromatic substitution
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tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
reaction mechanism
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tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
proposed mechanism: after formation of a FAD-OOH intermediate, the reactive chlorine is generated as a FAD-O-Cl intermediate. Chlorination of L-tryptophan proceeds by attack of the aromatic pi electrons on the intermediate in a two-electron mechanism and abstraction of a proton generates the final product
-
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tryptophan + FADH2 + chloride + O2 + H+ = 7-chloro-L-tryptophan + FAD + 2 H2O
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-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
redox reaction
reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
L-tryptophan:FADH2 oxidoreductase (7-halogenating)
In the bacterium Lechevalieria aerocolonigenes the enzyme catalyses the initial step in the biosynthesis of rebeccamycin [2]. Also acts on bromide ion.
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CAS REGISTRY NUMBER
COMMENTARY
198575-11-0
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain 39243. Halogenation requires the presence of RebF, which catalyzes the NADH-dependent reduction of FAD to provide FADH2 for the halogenase
SwissProt
strain 39243. Halogenation requires the presence of RebF, which catalyzes the NADH-dependent reduction of FAD to provide FADH2 for the halogenase
SwissProt
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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
tryptamine + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptamine + FAD + H2O
-
-
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + 2 H2O
-
-
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
-
-
-
?
tryptophan + FADH2 + O2 + Cl- + H+
7-chlorotryptophan + FAD + H2O
-
initial step of rebeccamycin biosynthesis
-
-
?
L-tryptophan + FADH2 + Br- + O2 + H+
7-bromo-L-tryptophan + FAD + H2O
-
-
-
-
?
L-tryptophan + FADH2 + Br- + O2 + H+
7-bromo-L-tryptophan + FAD + H2O
-
identity of product is confirmed by ESI-MS and 1H-NMR. Reaction is selective for the 7-position. Brominating activity is about 75% of chlorinating activity
-
?
L-tryptophan + FADH2 + Br- + O2 + H+
7-bromo-L-tryptophan + FAD + H2O
-
identity of product is confirmed by ESI-MS and 1H-NMR. Reaction is selective for the 7-position. Brominating activity is about 75% of chlorinating activity
-
?
L-tryptophan + FADH2 + Cl- + O2
7-chloro-L-tryptophan + FAD + H2O
-
formation of 7-chlorotryptophan as the initial step in the biosynthesis of antitumor agent rebeccamycin
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-
?
L-tryptophan + FADH2 + Cl- + O2
7-chloro-L-tryptophan + FAD + H2O
-
reaction of FADH2, Cl-, and O2 in the active site, involving active site Lys79, generates the powerful oxidant HOCl, which was presumed to carry out the chlorination reaction, formation of a long-living chlorinating intermediate, which remains on the enzyme after removal of FAD and transfers chlorine to tryptophan with kinetically competent rates, substrate binding structure, overview
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-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
-
-
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
identity of product is confirmed by ESI-MS and 1H-NMR
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
identity of product is confirmed by ESI-MS and 1H-NMR
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
-
-
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
regioselective reaction
-
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
the enzyme is involved in biosynthesis of pyrrolnitrin
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
-
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
rebeccamycin biosynthesis
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
-
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
-
-
-
-
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
chlorination of its natural substrate tryptophan exclusively at the 7-position, a position at which direct chemical chlorination is not possible
-
-
-
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
rebeccamycin biosynthesis
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
-
-
-
-
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
chlorination of its natural substrate tryptophan exclusively at the 7-position, a position at which direct chemical chlorination is not possible
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additional information
?
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first step in biosynthesis of rebeccamycin
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-
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additional information
?
-
O2 and presence of RebF, which catalyzes the NADH-dependent reduction of FAD to provide FADH2 for the halogenase, are required for reaction. 54% of available L-tryptophan are converted within 5 min when the reaction is prepapred anaerobically and O2 is introduced slowly. Reaction rate drops by 90% in air-saturated conditions. No substrate: fluoride, iodide
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-
-
additional information
?
-
O2 and presence of RebF, which catalyzes the NADH-dependent reduction of FAD to provide FADH2 for the halogenase, are required for reaction. 54% of available L-tryptophan are converted within 5 min when the reaction is prepapred anaerobically and O2 is introduced slowly. Reaction rate drops by 90% in air-saturated conditions. No substrate: fluoride, iodide
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additional information
?
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first step in pyrrolnitrin biosynthetic pathway
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-
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additional information
?
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Trp 7-hal can accept a number of different tryptophan, indole, and phenylpyrrole derivatives (e.g. 3-(2'-aminophenyl)pyrrole or monodechloroaminopyrrolnitrin), but only tryptophan is regioselectively chlorinated in the 7-position of the indole ring. With all the other compounds, the reaction proceeds with a relaxed regioselectivity
-
-
-
additional information
?
-
Trp 7-hal can accept a number of different tryptophan, indole, and phenylpyrrole derivatives (e.g. 3-(2'-aminophenyl)pyrrole or monodechloroaminopyrrolnitrin), but only tryptophan is regioselectively chlorinated in the 7-position of the indole ring. With all the other compounds, the reaction proceeds with a relaxed regioselectivity
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-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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 + FADH2 + Cl- + O2
7-chloro-L-tryptophan + FAD + H2O
-
formation of 7-chlorotryptophan as the initial step in the biosynthesis of antitumor agent rebeccamycin
-
-
?
L-tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
the enzyme is involved in biosynthesis of pyrrolnitrin
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + 2 H2O
-
-
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-L-tryptophan + FAD + H2O
-
-
-
-
?
tryptophan + FADH2 + O2 + Cl- + H+
7-chlorotryptophan + FAD + H2O
-
initial step of rebeccamycin biosynthesis
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
Q8KHZ8
rebeccamycin biosynthesis
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
Q9RPG3
chlorination of its natural substrate tryptophan exclusively at the 7-position, a position at which direct chemical chlorination is not possible
-
-
-
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
Q4KAM7
rebeccamycin biosynthesis
-
-
?
tryptophan + FADH2 + Cl- + O2 + H+
7-chloro-tryptophan + FAD + H2O
Q9RPG3
chlorination of its natural substrate tryptophan exclusively at the 7-position, a position at which direct chemical chlorination is not possible
-
-
-
additional information
?
-
-
first step in biosynthesis of rebeccamycin
-
-
-
additional information
?
-
-
first step in pyrrolnitrin biosynthetic pathway
-
-
-
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FADH2
-
required, purified enzyme does not contain flavin. FADH2 may be provided by a flavin reductase or by regeneration via the organometallic complex (pentamethylcyclopentadienyl)rhodium-bipyridine
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0499
tryptophan
-
His-tagged recombinant wild type enzyme, at 30°C, pH not specified in the publication
0.1986
tryptophan
-
His-tagged recombinant mutant enzyme F103A, at 30°C, pH not specified in the publication
1.785
tryptophan
-
His-tagged recombinant mutant enzyme H101A, at 30°C, pH not specified in the publication
1.814
tryptophan
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His-tagged recombinant mutant enzyme W455A, at 30°C, pH not specified in the publication
additional information
additional information
-
stopped-flow analysis of flavin intermediates
-
additional information
additional information
-
kinetics analysis of apo-enzyme and ligand-bound enzyme
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.018
tryptophan
Pseudomonas fluorescens
-
His-tagged recombinant mutant enzyme W455A, at 30°C, pH not specified in the publication
0.021
tryptophan
Pseudomonas fluorescens
-
His-tagged recombinant mutant enzyme H101A, at 30°C, pH not specified in the publication
0.05
tryptophan
Lechevalieria aerocolonigenes
-
ranges from 0.02 s-1 to 0.05 s-1 for different preparations, 25°C
0.067
tryptophan
Pseudomonas fluorescens
-
His-tagged recombinant mutant enzyme F103A, at 30°C, pH not specified in the publication
0.11
tryptophan
Pseudomonas fluorescens
-
His-tagged recombinant wild type enzyme, at 30°C, pH not specified in the publication
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
PrnA activities are determined after addition of flavin reductase (SsuE). Without reductase, fractions after elution from the molecular sieve column do not show any activity
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
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PDB
SCOP
CATH
ORGANISM
UNIPROT
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
61074
-
x * 61074, native protein, x * 61641, selenomethionine derivative, mass spectrometry
61641
-
x * 61074, native protein, x * 61641, selenomethionine derivative, mass spectrometry
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 61074, native protein, x * 61641, selenomethionine derivative, mass spectrometry
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
apo-enzyme or enzyme bound to FAD or L-tryptophan, X-ray diffraction structure determination and analysis at 2.08-2.3 A resolution
-
hanging drop method, structural analysis of RebH in its apo-form as well as in a complex with both tryptophan and FAD
-
hanging drop method, structural analysis of the enzyme in its apo-form as well as in a complex with both tryptophan and FAD at resolution of 2.5 A
-
protein without ligands and in presence of tryptophan and 7-chlorotryptophan
-
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F103A
-
the mutant shows increased Km and reduced kcat values compared to the wild type enzyme
H101A
-
the mutant shows increased Km and reduced kcat values compared to the wild type enzyme
W455A
-
the mutant shows increased Km and reduced kcat values compared to the wild type enzyme
additional information
additional information
gene disruption mutant, no production of pyrroindomycin B, but still production of pyrroindomycin A
additional information
-
gene disruption mutant, no production of pyrroindomycin B, but still production of pyrroindomycin A
-
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LINKS TO OTHER DATABASES (specific for EC-Number 1.14.19.9)
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