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Enzyme Nomenclature
Information on EC 1.13.11.46 - 4-hydroxymandelate synthase
for references in articles please use BRENDA:EC1.13.11.46
Word Map on EC 1.13.11.46
- 1.13.11.46
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benzylic
-
dioxygenation
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decarboxylation
- orientalis
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amycolatopsis
- homogentisate
- oxygenases
- deuterium
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carbon-carbon
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facial
-
1,2-shift
- vancomycin
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heterolytic
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charge-transfer
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aceto
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substructure
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biradical
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nonheme
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polycyclic
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ensuing
- hg
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ferryl
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
1.13.11.46
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RECOMMENDED NAME
GeneOntology No.
4-hydroxymandelate synthase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
4-hydroxyphenylpyruvate + O2 = (S)-4-hydroxymandelate + CO2
one oxygen from molecular oxygen is incorporated into the carboxyl group and one into the benzylic hydroxyl group
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4-hydroxyphenylpyruvate + O2 = (S)-4-hydroxymandelate + CO2
HMS uses Fe(IV)=O to perform hydroxylation of the benzylic carbon, reaction mechanism with electrophilic attack on the aromatic ring, and HMS catalytic cycle, overview
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4-hydroxyphenylpyruvate + O2 = (S)-4-hydroxymandelate + CO2
reaction mechanism, overview
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4-hydroxyphenylpyruvate + O2 = (S)-4-hydroxymandelate + CO2
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-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidative decarboxylation
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-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
4-hydroxyphenylpyruvate:oxygen oxidoreductase (decarboxylating)
Requires Fe2+. Involved in the biosynthesis of the vancomycin group of glycopeptide antibiotics.
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CAS REGISTRY NUMBER
COMMENTARY
280566-04-3
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
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4-hydroxyphenylpyruvate dioxygenase, HPPD, EC 1.13.11.27, and hydroxymandelate synthase 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
malfunction
additional information
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molecular docking and modeling, molecular dynamics and simulations by classical molecular dynamics simulations, simulated HMS-Fe(IV)-O-HPA species, overview
malfunction
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upon introduction of a steric barrier, which is suspected to obstruct the accommodation of the aromatic ring in the hydrophobic pocket during the final hydroxylation step, the racemization of product is obtained
malfunction
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upon introduction of a steric barrier, which is suspected to obstruct the accommodation of the aromatic ring in the hydrophobic pocket during the final hydroxylation step, the racemization of product is obtained
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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
4-hydroxymandelate + CO2
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-
-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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-
-
-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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alpha-keto acid dependent dioxygenase reaction
substrate of non-ribosomal peptide antibiotics such as vancomycin and chloroeremomycin
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?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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active site structure and 4-hydroxymandelate binding structure, overview
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-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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-
-
-
?
additional information
?
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substrate specificity, overview, Hms accepts a range of 2-oxo acids, whereby the presence of an aromatic substituent is crucial for efficient substrate turnover. A hydrophobic substrate binding pocket is identified as the likely determinant of substrate specificity. The enzyme shows high regioselectivity of oxygenation and a strong coupling efficiency of C-C bond cleavage and subsequent hydroxylation. The turnover number of Hms strongly correlates with substrate hydrophobicity. Quantitative structure activity relationship and in silico docking analyses, e.g. with (S)-mandelate and (R)-mandelate, overview
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-
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additional information
?
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substrate specificity, overview, Hms accepts a range of 2-oxo acids, whereby the presence of an aromatic substituent is crucial for efficient substrate turnover. A hydrophobic substrate binding pocket is identified as the likely determinant of substrate specificity. The enzyme shows high regioselectivity of oxygenation and a strong coupling efficiency of C-C bond cleavage and subsequent hydroxylation. The turnover number of Hms strongly correlates with substrate hydrophobicity. Quantitative structure activity relationship and in silico docking analyses, e.g. with (S)-mandelate and (R)-mandelate, overview
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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
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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-
-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
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-
-
-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
-
alpha-keto acid dependent dioxygenase reaction
substrate of non-ribosomal peptide antibiotics such as vancomycin and chloroeremomycin
-
?
4-hydroxyphenylpyruvate + O2
4-hydroxymandelate + CO2
-
-
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-[2-nitro-4-(triflouromethyl)benzoyl]-1,3-cyclohexanedione
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anaerobic conditions, complex with Fe2+ and enzyme, a herbicide/therapeutic that inhibits 4-hydroxyphenylpyruvate dioxygenase in a similar manner
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
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steady-state kinetic analysis, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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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
Streptomyces coelicolor (strain ATCC BAA-471 / A3(2) / M145)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40368
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alpha,alpha, 2 * 40368, gel filtration, electrospray mass spectrometry
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
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alpha,alpha, 2 * 40368, gel filtration, electrospray mass spectrometry
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hanging drop method, the crystal structure of the hydroxymandelate synthase/Co2+/hydroxymandelate complex determined to a resolution of 2.3 A
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant C-terminally strep-tagged enzyme from Escherichia coli strain BL21(DE3) by affinity chromatography
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recombinant wild-type and mutant enzymes by ammonium sulfate fractionation, anion echange chromatography, and gel filtration
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recombinant wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation, anion exchange chromatography, and gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of C-terminally strep-tagged enzyme in Escherichia coli strain BL21(DE3)
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expression of wild-type and mutant enzymes in Escherichia coli strain BL21(DE3)
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
I216N
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site-directed mutagenesis, the mutant shows increased catalytic efficiency compared to the wild-type enzyme, the mutant produces 90% 4-hydroxmandelate and 10% 4-hydroxyphenylacetate from 4-hydroxyphenylpyruvate, which differs from the wild-type, that does not produce any 4-hydroxyphenylacetate
S201A
T214P
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site-directed mutagenesis, mutant shows decreased catalytic efficiency compared to the wild-type enzyme
S201A
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site-directed mutagenesis, the mutant shows increased catalytic efficiency compared to the wild-type enzyme, the mutant produces 88% 4-hydroxmandelate and 12% 4-hydroxyphenylacetate from 4-hydroxyphenylpyruvate, which differs from the wild-type, that does not produce any 4-hydroxyphenylacetate
S201A
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site-directed mutagenesis, the mutant enzyme produces 3% 4-hydroxyphenylacetate, and 97% 4-hydroxymandelate, the benzylic carbon retains predominant sp3 character in the TS for the initial hydrogen abstraction
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LINKS TO OTHER DATABASES (specific for EC-Number 1.13.11.46)
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