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Information on EC 1.13.11.27 - 4-hydroxyphenylpyruvate dioxygenase and Organism(s) Streptomyces avermitilis and UniProt Accession Q53586
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1.13.11.27 4-hydroxyphenylpyruvate dioxygenaseIUBMB Comments
The Pseudomonas enzyme contains one Fe3+ per mole of enzyme; the enzymes from other sources may contain essential iron or copper.
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Word Map
- 1.13.11.27
-
syncytial
- viruses
- newcastle
- hn
- paramyxovirus
- epitope
- hemagglutinin-neuraminidase
- infant
- measles
- parainfluenza
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herbicide
-
sendai
- homogentisate
-
heptad
- hemagglutinin
- virion
-
fusogenic
- tyrosinemia
- metapneumovirus
-
prefusion
-
anti-f
-
palivizumab
-
weed
-
postfusion
- paramyxoviridae
- furin
- distemper
- ectodomains
- mumps
-
virus-cell
-
rsv-infected
-
six-helix
-
cleavability
-
formalin-inactivated
-
lasota
-
virus-neutralizing
-
virus-like
- morbillivirus
- panencephalitis
- ntbc
-
anti-rsv
-
nipah
-
velogenic
- nucleopolyhedrovirus
- drug development
- alkaptonuria
- diagnostics
-
thomsen-friedenreich
- agriculture
- environmental protection
- rinderpest
-
live-attenuated
- medicine
-
merger
- fumarylacetoacetate
The taxonomic range for the selected organisms is: Streptomyces avermitilis
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
f protein, 4-hydroxyphenylpyruvate dioxygenase, tf-ag, p-hydroxyphenylpyruvate dioxygenase, 4-hppd, 4-hydroxyphenylpyruvic acid dioxygenase, 4hppd, athppd, legiolysin, p-hydroxyphenylpyruvate hydroxylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4-HPPD
-
-
-
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4-hydroxyphenylpyruvic acid dioxygenase
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-
-
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4HPPD
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-
-
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EC 1.14.2.2
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-
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EC 1.99.1.14, formerly
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-
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F Alloantigen
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-
-
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F protein
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-
-
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F-antigen homolog
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-
-
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HPD
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-
-
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HPPD
HPPDase
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-
-
-
Legiolysin
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-
-
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oxygenase, 4-hydroxyphenylpyruvate di-
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-
-
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p-hydroxyphenylpyruvate dioxygenase
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-
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p-hydroxyphenylpyruvate hydroxylase
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-
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p-hydroxyphenylpyruvate oxidase
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-
-
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p-hydroxyphenylpyruvic acid hydroxylase
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p-hydroxyphenylpyruvic hydroxylase
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-
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p-hydroxyphenylpyruvic oxidase
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-
-
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T-cell reactive protein
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-
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TF-AG
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-
-
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HPPD
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
dioxygen reactivity and the common decarboxylation half reaction, and the hydroxylation half reaction, mechanisms, detailed overview
4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
addition of substrate and oxygen to the holoenzyme is formally random, holo-enzym in complex with substrate has a 3600-fold increase in oxygen reactivity
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4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
mechanism of oxygen binding and activation, structural relationship to other dioxygenases
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4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
reaction mechanism, overview
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4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
The data of the rapid acid quench followd by HPLC product analysis, indicate that the homogenisate product is formed during one turnover, as the amount of product is equivalent to the enzyme-substrate complex at 191 ms.
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4-hydroxyphenylpyruvate + O2 = homogentisate + CO2
direct involvement of the arene oxide intermediate to the reaction mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
decarboxylation
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-
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redox reaction
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-
-
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hydroxylation
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-
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side-chain migration
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PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating)
The Pseudomonas enzyme contains one Fe3+ per mole of enzyme; the enzymes from other sources may contain essential iron or copper.
CAS REGISTRY NUMBER
COMMENTARY
9029-72-5
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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
4-hydroxyphenylpyruvate + O2
homogentisate + CO2
-
-
-
?
additional information
?
-
-
Single turnover kinetics are observed spectrophotometrically by mixing equal volumes of the anaerobic enzyme-substrate complex and solutions containing molecular oxygen in the presence of saturating HPP using a stopped-flow spectrophotometer. k1 = 7.4 x 100000 /M/s, k2 = 74 /s, k3 = 13.2 /s, k4 = 1.6 /s, indicating the accumulation of three catalytic intermediates. The kinetic data observed with substrate substituted with deutererons for aromatic protons are not significantly different from those observed with the proteo substrate. The final phase in catalysis (k4), decreases to 0.7 /s in the presence of deuterium oxide solvent, indicating the involvement of a solvent-derived proton in this step.
-
-
?
4-hydroxyphenylpyruvate + O2
homogentisate + CO2 + 4-hydroxyphenylacetate
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-
the wild-type enzyme produces 85% homogentisate and 15% 4-hydroxyphenylacetate
-
?
4-hydroxyphenylpyruvate + O2
homogentisate + CO2 + 4-hydroxyphenylacetate
-
-
the wild-type enzyme produces 90% homogentisate, 1% quinolacetate, and 9% 4-hydroxyphenylacetate
-
?
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
4-hydroxyphenylpyruvate + O2
homogentisate + CO2
-
-
-
?
4-hydroxyphenylpyruvate + O2
homogentisate + CO2 + 4-hydroxyphenylacetate
-
-
the wild-type enzyme produces 85% homogentisate and 15% 4-hydroxyphenylacetate
-
?
4-hydroxyphenylpyruvate + O2
homogentisate + CO2 + 4-hydroxyphenylacetate
-
-
the wild-type enzyme produces 90% homogentisate, 1% quinolacetate, and 9% 4-hydroxyphenylacetate
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Iron
distorted square-pyramidal coordination with Glu349, His187, His270
Fe2+
-
a Fe(II)-dependent dioxygenase, Fe2+ is involved in the catalytic mechanism binding to the substrate, overview
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione
-
nitisinone
i.e. orfadin or NTBC, bidentate coordination of NTBC with the HPPD active site ferrous ion, enzyme-bound crystal structure, overview
2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione
-
mechanism of binding, enzyme-Fe(II)-inhibitor complex does not oxidize, dissociation rate constant is essentially zero
additional information
inhibition mechanism of enzyme HPPD, detailed overview
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.027
4-hydroxyphenylpyruvate
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pH 7.0, 25°C, wild-type enzyme and mutant N245I
11
4-hydroxyphenylpyruvate
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Solvent is H2O. Steady-state analyses of 4-hydroxyphenylpyruvate dioxygenase using proteo-HPP, 2,3,5,6-tetradeutero-HPP, and proteo-HPP in deuterium oxide are carried out in 1 ml assays on a Hasetech oxygen electrode. The assay mixture include ferrous sulfate (10 microM), DTT (1mM), HPPD (500 nM), and HPP (0-1 mM) in 20 mM HEPES, pH (pD) 7.0, under conditions of atmospheric oxygen (350 microM at 5°C)
22
4-hydroxyphenylpyruvate
-
Solvent is H2O. Steady-state analyses of 4-hydroxyphenylpyruvate dioxygenase using proteo-HPP, 2,3,5,6-tetradeutero-HPP, and proteo-HPP in deuterium oxide are carried out in 1 ml assays on a Hasetech oxygen electrode. The assay mixture include ferrous sulfate (10 microM), DTT (1mM), HPPD (500 nM), and HPP (0-1 mM) in 20 mM HEPES, pH (pD) 7.0, under conditions of atmospheric oxygen (350 microM at 5°C)
54
4-hydroxyphenylpyruvate
-
Solvent is D2O. Steady-state analyses of 4-hydroxyphenylpyruvate dioxygenase using proteo-HPP, 2,3,5,6-tetradeutero-HPP, and proteo-HPP in deuterium oxide are carried out in 1 ml assays on a Hasetech oxygen electrode. The assay mixture include ferrous sulfate (10 microM), DTT (1mM), HPPD (500 nM), and HPP (0-1 mM) in 20 mM HEPES, pH (pD) 7.0, under conditions of atmospheric oxygen (350 microM at 5°C)
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
with substrate 2,3,5,6-tetraproteo 4-hydroxyphenylpyruvate and the solvent H2O Vmax = 1.9/s, with substrate 2,3,5,6-tetradeutero 4-hydroxyphenylpyruvate and the solvent H2O Vmax = 1.8/s, with substrate 2,3,5,6-tetraproteo 4-hydroxyphenylpyruvate and the solvent D2O Vmax = 0.86/s
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
4-hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS, EC 1.13.11.46) are outliers within the 2-oxo acid dependent oxygenase (aKAO) family. HPPD and HMS catalyze the chemistry of the majority of enzymes within the aKAO family but are clearly mechanistically convergent, having a grossly different structural topology. Some of the unique characteristics of HPPD and HMS have elucidated select parts of the catalytic cycle that are obscured in other family members. Moreover, the inhibitory chemistry of HPPD is a phenomenon with ever-expanding relevance across all kingdoms of life
evolution
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4-hydroxyphenylpyruvate dioxygenase and hydroxymandelate synthase, HMS, EC 1.13.11.46, catalyze similar reactions using the same substrates, 4-hydroxyphenylpyruvate and dioxygen. Initially, both enzymes reduce and activate dioxygen in order to decarboxylate 4-hydroxyphenylpyruvate, yielding 4-hydroxyphenylacetate, CO2, and an activated oxo intermediate Both enzymes then hydroxylate 4-hydroxyphenylacetate but do so in different positions
additional information
additional information
-
substrate binding, structure modeling, structure comparisons, quantum mechanical/molecular mechanical calculations of the enzyme-substrate complex and key reaction intermediates, overview. Residues Ser201, Asn216, Gln226, Gln230, and Gln305 are important for catalysis
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Fe(II)-form in complex with inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N245S
site-directed mutagenesis, the mutant produces quinolacetic acid as reaction product
F364I
-
site-directed mutagenesis, the mutant enzyme produces 47% homogentisate, 15% 4-hydroxyphenylacetate, and 19% quinolacetate, which differs from the wild-type activity
N245D
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site-directed mutagenesis, the mutant enzyme produces 52% homogentisate and 26.8% 4-hydroxyphenylacetate, and 21.2% quinolacetate, which differs from the wild-type activity
N245I
-
site-directed mutagenesis, the mutant enzyme produces 13% homogentisate and 87% 4-hydroxyphenylacetate, which differs from the wild-type activity
N245Q
N245S
-
site-directed mutagenesis, the mutant enzyme produces 3.4% homogentisate and 6.6% 4-hydroxyphenylacetate, and 90% quinolacetate, which differs from the wild-type activity
P243T
S230A
N245Q
-
site-directed mutagenesis, the mutant enzyme produces 44.5% homogentisate and 52% 4-hydroxyphenylacetate, and 4% quinolacetate, which differs from the wild-type activity
N245Q
-
site-directed mutagenesis, the mutant enzyme produces 52% homogentisate and 45% 4-hydroxyphenylacetate, and 3% quinolacetate, which differs from the wild-type activity
P243T
-
site-directed mutagenesis, the mutant enzyme produces 13% homogentisate, 8.7% 4-hydroxyphenylacetate, and 78% quinolacetate, which differs from the wild-type activity
P243T
-
site-directed mutagenesis, the mutant enzyme produces 8.4% homogentisate, 46.5% 4-hydroxyphenylacetate, and 45% quinolacetate, which differs from the wild-type activity
S230A
-
site-directed mutagenesis, the mutant enzyme produces 11.6% homogentisate, 30.6% 4-hydroxyphenylacetate, and 57.8% quinolacetate, which differs from the wild-type activity
S230A
-
site-directed mutagenesis, the mutant enzyme produces 7% homogentisate, 57% 4-hydroxyphenylacetate, and 36% quinolacetate, which differs from the wild-type activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant enzymes by ammonium sulfate fractionation, anion exchange chromatography, and gel filtration
-
recombinant wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation, anion exchange chromatography, and gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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mechanism of binding of the inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione used to treat type I tyrosinemia. Enzyme-Fe(II)-inhibitor complex does not oxidize, dissociation rate constant is essentially zero
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kavana, M.; Moran, G.R.
Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione
Biochemistry
42
10238-10245
2003
Streptomyces avermitilis
Johnson-Winters, K.; Purpero, V.M.; Kavana, M.; Nelson, T.; Moran, G.R.
(4-Hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis: the basis for ordered substrate addition
Biochemistry
42
2072-2080
2003
Streptomyces avermitilis
Brownlee, J.M.; Johnson-Winters, K.; Harrison, D.H.; Moran, G.R.
Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC
Biochemistry
43
6370-6377
2004
Streptomyces avermitilis (Q53586)
Gunsior, M.; Ravel, J.; Challis, G.L.; Townsend, C.A.
Engineering p-hydroxyphenylpyruvate dioxygenase to a p-hydroxymandelate synthase and Evidence for the proposed benzene oxide intermediate in homogentisate formation
Biochemistry
43
663-674
2004
Streptomyces avermitilis (Q53586), Streptomyces avermitilis
Neidig, M.L.; Kavana, M.; Moran, G.R.; Solomon, E.I.
CD and MCD studies of the non-heme ferrous active site in (4-hydroxyphenyl)pyruvate dioxygenase: correlation between oxygen activation in the extradiol and alpha-KG-dependent dioxygenases
J. Am. Chem. Soc.
126
4486-4487
2004
Streptomyces avermitilis
Johnson-Winters, K.; Purpero, V.M.; Kavana, M.; Moran, G.R.
Accumulation of multiple intermediates in the catalytic cycle of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis
Biochemistry
44
7189-7199
2005
Streptomyces avermitilis
Shah, D.D.; Conrad, J.A.; Heinz, B.; Brownlee, J.M.; Moran, G.R.
Evidence for the mechanism of hydroxylation by 4-hydroxyphenylpyruvate dioxygenase and hydroxymandelate synthase from intermediate partitioning in active site variants
Biochemistry
50
7694-7704
2011
Streptomyces avermitilis
Shah, D.; Conrad, J.; Moran, G.
Intermediate partitioning kinetic isotope effects for the NIH shift of 4-hydroxyphenylpyruvate dioxygenase and the hydroxylation reaction of hydroxymandelate synthase reveal mechanistic complexity
Biochemistry
52
6097-6107
2013
Streptomyces avermitilis
Raspail, C.; Graindorge, M.; Moreau, Y.; Crouzy, S.; Lefebvre, B.; Robin, A.Y.; Dumas, R.; Matringe, M.
4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme
J. Biol. Chem.
286
26061-26070
2011
Arabidopsis thaliana, Daucus carota, Pseudomonas fluorescens, Streptomyces avermitilis
Moran, G.
4-Hydroxyphenylpyruvate dioxygenase and hydroxymandelate synthase exemplars of the alpha-keto acid dependent oxygenases
Arch. Biochem. Biophys.
544
58-68
2014
Pseudomonas fluorescens, Paracoccidioides brasiliensis, Homo sapiens (P32754), Arabidopsis thaliana (P93836), Streptomyces avermitilis (Q53586), Streptomyces avermitilis ATCC 31267 (Q53586)
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