1.14.16.1: phenylalanine 4-monooxygenase
This is an abbreviated version!
For detailed information about phenylalanine 4-monooxygenase, go to the full flat file.
Word Map on EC 1.14.16.1
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1.14.16.1
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phenylketonuria
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hyperphenylalaninemia
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bh4
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error
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pterins
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inborn
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children
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hydroxylases
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neurotransmitter
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province
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tetrahydropterins
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counsel
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intellectual
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dopamine
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l-tyrosine
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genotype-phenotype
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prenatal
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serotonin
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dihydropteridine
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caucasian
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catecholamine
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hepatocytes
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sepiapterin
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genotype-based
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quinonoid
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non-heme
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chromobacterium
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neopterin
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ligation-dependent
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dihydrochloride
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neuropsychological
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lysolecithin
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lifelong
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phenylpyruvate
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dopa
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cyclohydrolase
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molecular biology
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rflps
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p-chlorophenylalanine
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dihydrobiopterin
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hypopigmentation
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s-oxidation
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pteridine
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violaceum
- 1.14.16.1
- phenylketonuria
- hyperphenylalaninemia
- bh4
- error
- pterins
-
inborn
- children
- hydroxylases
-
neurotransmitter
-
province
- tetrahydropterins
-
counsel
-
intellectual
- dopamine
- l-tyrosine
-
genotype-phenotype
-
prenatal
- serotonin
- dihydropteridine
-
caucasian
- catecholamine
- hepatocytes
- sepiapterin
-
genotype-based
-
quinonoid
-
non-heme
-
chromobacterium
- neopterin
-
ligation-dependent
- dihydrochloride
-
neuropsychological
- lysolecithin
-
lifelong
- phenylpyruvate
- dopa
-
cyclohydrolase
- molecular biology
-
rflps
- p-chlorophenylalanine
- dihydrobiopterin
-
hypopigmentation
-
s-oxidation
- pteridine
- violaceum
Reaction
Synonyms
cePAH, DicPAH, EC 1.14.3.1, EC 1.99.1.2, HPAH, L-phenylalanine 4-hydroxylase, oxygenase, phenylalanine 4-mono-, P4H, PAH, PheH, phenylalaninase, phenylalanine 4-hydroxylase, phenylalanine hydroxylase, phenylalanine monooxygenase, PheOH, phhA
ECTree
1.14.16.1 phenylalanine 4-monooxygenaseAdvanced search results
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results (Engineering
Engineering on EC 1.14.16.1 - phenylalanine 4-monooxygenase
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PROTEIN VARIANTS 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Q215K/N216Y
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humanized mutant Q215K/N216Y of cePAH binds 1.4 L-Phe/subunit. This mutant also displays high catalytic activity and certain positive cooperativity for L-Phe. Km for cofactor tetrahydrobiopterin higher compared to wild-type, [S]0.5 (L-Phe) lower compared to wild-type, Vmax (L-Phe) higher compared to wild-type
D139A
the catalytic efficiency for L-phenylalanine is 81fold lower than that of the wild type enzyme
D139E
the catalytic efficiency for L-phenylalanine is 7fold lower than that of the wild type enzyme
D139N
the catalytic efficiency for L-phenylalanine is 17fold lower than that of the wild type enzyme
F258A
the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
G221A
the half-life of the mutant at 50°C is 16.8 min, which is increased by 0.9-times compared to the wild type enzyme
I234D
-
mutant shows decreased kcat value for 6,7-dimethyltetrahydropterin compared to the wild type enzyme
K94R
the half-life of the mutant at 50°C is 26.2 min, which is increased by 1.9-times compared to the wild type enzyme
K94R/G221A
the residual activity of the mutant is improved to 65.6% after keeping at 50°C for 1 h, which is 6.6 time higher than the wild type enzyme
L101A
the mutant shows 26% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101C
the mutant shows 47% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101D
the mutant shows 5% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101E
the mutant shows 9% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101F
the mutant shows 133% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101G
the mutant shows 20% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101H
the mutant shows 16% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101I
the mutant shows 51% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101K
the mutant shows 29% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101M
the mutant shows 102% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101N
the mutant shows 15% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101P
the mutant shows 9% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101Q
the mutant shows 30% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101R
the mutant shows 29% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101S
the mutant shows 28% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101T
the mutant shows 26% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101V
the mutant shows 26% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101W
the mutant shows 55% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101Y
the mutant shows 153% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
L101Y/W180F
the double mutant displays higher L-tryptophan hydroxylation activity than the wild type enzyme with a 5.2fold increase in kcat
S230P
the mutant shows strongly decreased activity and a marked decrease in the affinity for L-phenylalanine
T254A
the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
W180A
the mutant shows 66% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180C
the mutant shows 119% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180D
the mutant shows 3% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180E
the mutant shows 6% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180F
the mutant shows 204% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180G
the mutant shows 8% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180H
the mutant shows 73% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180I
the mutant shows 113% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180K
the mutant shows 4% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180L
the mutant shows 174% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180M
the mutant shows 166% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180N
the mutant shows 49% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180P
the mutant shows 15% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180Q
the mutant shows 17% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180R
the mutant shows 85% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180S
the mutant shows 46% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180T
the mutant shows 44% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180V
the mutant shows 155% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
W180Y
the mutant shows 115% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
Y155A
the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
Y179A
-
stability and metal binding comparable to wild-type, kcat-value one order of magnitude lower than wild-type, KM-value of L-phenylalanine increases by 10-fold
Y179F
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stability and metal binding comparable to wild-type, kcat-value one order of magnitude lower than wild-type
F258A
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the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
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S230P
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the mutant shows strongly decreased activity and a marked decrease in the affinity for L-phenylalanine
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T254A
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the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
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Y155A
-
the mutant shows decreased activity and a marked decrease in the affinity for L-phenylalanine
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L101A
-
the mutant shows 26% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
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L101F
-
the mutant shows 133% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
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L101I
-
the mutant shows 51% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
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L101W
-
the mutant shows 55% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
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L101Y
-
the mutant shows 153% relative L-tryptophan hydroxylation activity compared to the wild type enzyme
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A104D
A259T
A259V
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the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
A300S
A313T
A395G
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
A403V
A447P
C237D
D143G
mutant with a mild misfolding defect associated with phenylketonuria
D415N
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naturally occuring missense mutation causing a mild phenylketonuria phenotype
DELTA1-102
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mutant lacking the first 102 residues corresponding to the N-terminal regulatory domain. 96% of the truncated mutant exist as a tetramer. On coexpression of wild-type-hPAH and the N-terminally truncated form DELTA1-102 (~95% tetramer), heterotetramers, as a result of an assembly of two different homodimers, are isolated. The recovered (wild-type)/(DELTA1-102 mutant)-hPAH heterotetramers reveal a catalytic activity deviating significantly from that calculated by averaging the respective recombinant homotetrameric forms. The heterotetramer assembly also results in conformational changes in the WT-hPAH protomer, as detected by trypsin limited proteolysis
DELTA1-102/DELTAC24
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mutant lacking the first 102 residues corresponding to the N-terminal regulatory domain and the last 24 residues at the C-terminal end corresponding to the tetramerisation motif. 81% of the truncated mutant exist as a dimer and 17% as an aggregated form. On co-expression of wild-type-hPAH (50% tetramer, 10% dimer) and the N- and C-terminally truncated form DELTA1-102/DELTAC24 (80% dimer) no heterodimers is recovered
DELTA103-427
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dimeric double-truncated form: the dimeric variant 103-427 shows a Vmax (1980 nmol Tyr/min/mg protein) comparable with that of the non-activated wild-type PAH, which does not change markedly upon L-Phe preincubation (2421 nmol Tyr/min/mg protein)
E178G
E178G/Q232E
the mutant shows 55% activity compared to the wild type enzyme
E280K
E390G
E390G/R261Q
the mutant shows 63% activity compared to the wild type enzyme
E76G
F161S
F331S
the mutant shows residual enzymatic activity in vitro compared to the wild type enzyme
F382L
naturally occuring mutation and site-directed mutagenesis, the mutant shows 44% reduced activity compared to the wild-type enzyme, analysis of structural alterations
F39L
F39L/F55fsdelT
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes an atypical form of phenylketonuria
F39L/P281L
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naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes the classical form of phenylketonuria
F39L/R408W
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naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes the classical form of phenylketonuria
G103S
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site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, the mutant shows highly reduced activity compared to the wild-type
G247V
G332V
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site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, inactive mutant
G33A
increased basal activity, reduced activation by preincubation with substrate
G33V
increased basal activity, reduced activation by preincubation with substrate
G46S
H271Q
-
naturally occuring knockout missense mutation leading to a severe phenylketonuria phenotype
I174T
I174V
-
naturally occuring missense mutation causing a mild phenylketonuria phenotype
I65S
I65T
I65T/R261Q
the mutant shows 19.5% activity compared to the wild type enzyme
I65T/R408W
I65T/R68S
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naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes a mild form of phenylketonuria
I95F
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naturally occuring missense mutation causing a mild phenylketonuria phenotype
I97L
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and is involved in the disorder hyperphenylalaninemia
K113P
increased basal activity, reduced activation by preincubation with substrate, increase in positive cooperativity
K398N
naturally occuring mutation and site-directed mutagenesis, the mutant shows 45% reduced activity compared to the wild-type enzyme, analysis of structural alterations
L197F
-
naturally occuring knockout missense mutation leading to a severe phenylketonuria phenotype
L212P
L249F
L249P
L255S
L293M
-
site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, the mutant shows reduced activity and no response to tetrahydrobiopterin compared to the wild-type
L311P
L348V
L358F
the mutant shows residual enzymatic activity in vitro compared to the wild type enzyme
L48S
L48S/R261Q
the mutant shows 35% activity compared to the wild type enzyme
N223D
low basal activity, little activation by preincubation with substrate, increase in positive cooperativity
N223Y
naturally occuring mutation and site-directed mutagenesis, the mutant shows 30% reduced activity compared to the wild-type enzyme, analysis of structural alterations
N32D
low basal activity, close to normal activation by preincubation with substrate
N426D
low basal activity, close to normal activation by preincubation with substrate
P122Q
-
the mutant with wild type activity exhibits less than 50% of wild type protein level
P225T
P281L
P366H
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
P384S/R408W
the mutant shows 56.1% activity compared to the wild type enzyme
P416Q
the mutant retains significant catalytic activity yet is observed in classic and moderate phenylketonuria patients
P69S
-
site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, the mutant shows reduced activity compared to the wild-type
Q419R
naturally occuring mutation and site-directed mutagenesis, the mutant shows 29% reduced activity compared to the wild-type enzyme, analysis of structural alterations
R111X
R155H
R157N
-
the mutant with wild type activity exhibits less than 50% of wild type protein level
R158Q
R158Q/R261Q
the mutant shows 23% activity compared to the wild type enzyme
R158W
R176X
R241C
R243Q
R243X
exon 6 C727T mutation naturally occuring in phenylketonuria patients from the Cukurova region in Turkey, sequence determination and analysis
R252G
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
R252Q
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
R252W
R261P
R261Q
R270K
R297L
naturally occuring mutation and site-directed mutagenesis, the mutant shows 58% reduced activity compared to the wild-type enzyme, analysis of structural alterations
R408Q
R408W
R408W/A300S
the mutant shows 18% activity compared to the wild type enzyme
R408W/I283F
the mutant shows 2% residual activity compared to the wild type enzyme
R408W/I306V
the mutant shows 18% residual activity compared to the wild type enzyme
R408W/pA403V
the mutant shows 20% residual activity compared to the wild type enzyme
R408W/R158Q
R408W/R261Q
the mutant shows 18% activity compared to the wild type enzyme
R408W/R297H
the mutant shows 15% residual activity compared to the wild type enzyme
R408W/Y414C
the mutant shows 40% activity compared to the wild type enzyme
R413P
R53H
-
site-directed mutagenesis, the mutation occurs naturally in humans altering the tetrahydrobiopterin responsiveness, the mutant shows reduced activity and dimer stability compared to the wild-type
R68S
R68S/R408W
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes an atypical form of phenylketonuria
R71C
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and is involved in the disorder hyperphenylalaninemia
R86S
-
for the variants R68S and V106A, a Vmax comparable with the activated wild-type PAH is found without L-Phe preincubation, and no further increase is measured when the substrate is present. R68S and V106A without L-Phe preincubation show lower cofactor affinities than the non-activated wild-type PAH. Values are at the same level as determined for the L-Phe preincubated wild-type PAH
S196Y
the mutant shows about 20% activity compared to the wild type enzyme
S231F
the missense phenylalanine hydroxylase gene mutation causes complete loss of enzymatic activity in vitro (residual enzyme activity in vitro is about 1%) as it drastically reduces stability and activity of the PAH enzyme, the mutant enzyme is not activated by pre-incubation with L-phenylalanine substrate
S348L
instable enzyme forming aggregates after expression in Escherichia coli in the presence of GroESL
S349P
S391I
-
site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, inactive mutant
T380M
the mutant shows about 25% activity compared to the wild type enzyme
T427P
V106A
-
for the variants R68S and V106A, a Vmax comparable with the activated wild-type PAH is found without L-Phe preincubation, and no further increase is measured when the substrate is present. R68S and V106A without L-Phe preincubation show lower cofactor affinities than the non-activated wild-type PAH. Values are at the same level as determined for the L-Phe preincubated wild-type PAH
V245A/R261Q
the mutant shows 55% activity compared to the wild type enzyme
V379D/H264Q
the mutant shows significant activity at tyrosine hydroxylation and a 3000fold decrease in preference for phenylalanine over tyrosine as the substrate
V388M
Y138A
the mutant shows reduced catalytic efficiency (about 38%) compared to the wild type enzyme
Y138E
the mutant shows reduced catalytic efficiency (about 15%) compared to the wild type enzyme
Y138F
the mutant shows reduced catalytic efficiency (about 55%) compared to the wild type enzyme
Y138K
the mutant shows severely reduced catalytic efficiency (about 5%) compared to the wild type enzyme
Y204C
Y325A
Y325F
Y325L
-
stable, similar yields and oligomeric distribution as wild-type, reduced specific activity, decreased coupling efficiency and decreased iron content, no positive cooperativity for L-phenylalanine
Y356X
Y386C
exon 11 A1157G mutation naturally occuring in phenylketonuria patient from the Cukurova region in Turkey, sequence determination and analysis
Y414C
Y414C/R261Q
the mutant shows 64% activity compared to the wild type enzyme
A322S/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
A47G
the mutation decreases the affinity of the catalytic domain for L-phenylalanine compared to the wild type
DELTA1-117
mutant lacking the first 117 amino acids containing only the catalytic and tetramerization domains: the effects of phenylalanine on the hydrogen/deuterium exchange kinetics are limited to peptides surrounding the binding site for the amino acid substrate
E280A
-
site-directed mutagenesis of catalytic core mutant DELTA117PheH, 70% reduced activity but unaltered isotopic effects of isotope substrates
E330H
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows over 80% reduced activity compared to the wild-type enzyme
E330Q
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows over 80% reduced activity compared to the wild-type enzyme
E44Q
the mutation decreases the affinity of the catalytic domain for L-phenylalanine compared to the wild type and leads to loss of activity
F263A
-
site-directed mutagenesis of catalytic core mutant DELTA117PheH, 85% reduced activity but unaltered isotopic effects of isotope substrates
H264Q/V379D
H264Q/Y277H/V379D
H285E
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows over 80% reduced activity compared to the wild-type enzyme
H285Q
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows 80% reduced activity compared to the wild-type enzyme
H290E
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows over 80% reduced activity compared to the wild-type enzyme
H290Q
-
site-directed mutagenesis of a metal ligand binding residue, the mutant enzyme shows over 80% reduced activity compared to the wild-type enzyme
H64N
the mutation decreases the affinity of the catalytic domain for L-phenylalanine compared to the wild type
L293M
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
L48V
the mutation decreases the affinity of the catalytic domain for L-phenylalanine compared to the wild type
L62V
the mutation decreases the affinity of the catalytic domain for L-phenylalanine compared to the wild type and leads to loss of activity
R270K
S16E
-
slightly higher Km for tetrahydrobiopterin than wild-type, approx. 3fold higher Vmax with phenylalanine
S16N
-
slightly higher Km for tetrahydrobiopterin than wild-type, approx. 3fold higher Vmax with phenylalanine
S16Q
-
slightly higher Km for tetrahydrobiopterin than wild-type, similar Vmax with phenylalanine
S251A
-
truncated enzyme containing the catalytic domain, no tyrosine hydroxylation activity
S251A/H264Q
-
truncated enzyme containing the catalytic domain, no tyrosine hydroxylation activity
S251A/H264Q/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
S251A/H264Q/Y277H
-
truncated enzyme containing the catalytic domain, no tyrosine hydroxylation activity
S251A/H264Q/Y277H/A322S
-
truncated enzyme containing the catalytic domain, no tyrosine hydroxylation activity
S251A/H264Q/Y277H/A322S/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
S251A/H264Q/Y277H/A322S/V379D/Y356H
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
S251A/H264Q/Y277H/A322S/V379D/Y356H/L293M
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
S251A/H264Q/Y277H/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
S251A/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
V379D
Y277H/V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
W179/L98Y
-
the mutant shows 46% activity with L-phenylalanine and 1207% activity with L-tryptophan compared to the wild type enzyme
W179F
-
the mutant shows 80% activity with L-phenylalanine and 1739% activity with L-tryptophan compared to the wild type enzyme
W179F/L98Y/Y231C
-
the mutant shows 17% activity with L-phenylalanine and 570% activity with L-tryptophan compared to the wild type enzyme
W179F/Y231C
-
the mutant shows 52% activity with L-phenylalanine and 952% activity with L-tryptophan compared to the wild type enzyme
additional information
A104D
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and is involved in the disorder hyperphenylalaninemia
A104D
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to mild phenyletonuria
A259T
-
the mutant with wild type activity exhibits less than 50% of wild type protein level
A300S
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
A313T
the mutant displays 20-30% lower catalytic activity than the wild type enzyme
A403V
-
frequent naturally occuring mutation involved in enzyme deficiency and BH4-responsive hyperphenylalaninemia and/or phenylketonuria
A403V
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
A447P
-
site-directed mutagenesis, the mutation occurs naturally in phenylketonuria patients from Korea, the mutant shows highly reduced activity compared to the wild-type
E178G
exon 6 A533G mutation naturally occuring in phenylketonuria patients from the Cukurova region in Turkey, sequence determination and analysis
F161S
-
the mutant with wild type activity exhibits less than 50% of wild type protein level
F39L
-
the mutant has approximately 3fold higher specific activity than the wild type enzyme and leads to moderate phenyletonuria
G46S
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and is involved in the disorder hyperphenylalaninemia
G46S
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
G46S
the mutant shows lower allosteric Phe-binding ability compared to the wild type enzyme
I174T
the mutation results in the classical phenylketonuria phenotype expressing 0.2-1.8% of the wild type PAH activity when using L-phenylalanine as substrate, and has less 0.1% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as the substrate
I174T
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine or L-Phe) compared to wild-type
I65T
naturally occuring mutation involved in hyperphenylalaninemia of heterozygous patients, sequence analysis, the heterologous mutant shows reduced activity compared to the wild-type enzyme
I65T
-
frequent naturally occuring mutation involved in enzyme deficiency and BH4-responsive hyperphenylalaninemia and/or phenylketonuria
I65T
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme, but the mutant can be rescued by co-expression of chaperones GroEL and GroES
I65T
the mutant shows increased specific activity using L-phenylalanine as substrate and decreased specific activity using S-carboxymethyl-L-cysteine compared to the wild type enzyme
I65T
the S-oxidation of S-carboxymethyl-L-cysteine is dramatically reduced in the 5,6,7,8-tetrahydro-L-biopterin responsive mutant I65T possessing 1.2-2.0% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as substrate and expressing 23-76% of the wild type PAH activity when L-phenylalanine is used as the substrate
I65T
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine) no difference in Km (L-Phe) compared to wild-type
I65T
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to moderate phenyletonuria
I65T/R408W
-
naturally occuring mutation in the regulatory domain, that affects enzyme activity and causes the classical form of phenylketonuria
I65T/R408W
the mutant shows 15% activity compared to the wild type enzyme
L212P
the mutant shows about 20% activity compared to the wild type enzyme
L249F
the mutant shows about 55% activity compared to the wild type enzyme
L249P
the mutant shows about 5% activity compared to the wild type enzyme
L311P
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
L348V
25% activity after expression in Escherichia coli in the absence of GroESL, 55% in the presence of GroESL, 77% activity after expression in COS cells at 27°C
L348V
the mutant retains significant catalytic activity yet is observed in classic and moderate phenylketonuria patients
L48S
-
frequent naturally occuring mutation involved in enzyme deficiency and BH4-responsive hyperphenylalaninemia and/or phenylketonuria
L48S
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
L48S
-
the mutant has approximately 3fold higher specific activity than the wild type enzyme and leads to moderate phenyletonuria
P225T
-
naturally occuring knockout missense mutation leading to a severe phenylketonuria phenotype
P281L
exon 7 C842T mutation naturally occuring in phenylketonuria patient from the Cukurova region in Turkey, sequence determination and analysis
P281L
-
naturally occuring missense mutation causing a severe phenylketonuria phenotype
P281L
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
R155H
the mutant displays low PAH activity and decreased apparent affinity for L-Phe yet is observed in mild hyperphenylalaninaemia, mutant does not display kinetic instability, as it is stabilized by (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin similarly to wild type enzyme
R158Q
-
naturally occuring missense mutation causing a severe phenylketonuria phenotype
R158Q
the mutation results in the classical phenylketonuria phenotype expressing 0.2-1.8% of the wild type PAH activity when using L-phenylalanine as substrate, and has less 0.1% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as the substrate
R158Q
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine or L-Phe) compared to wild-type
R158W
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
R241C
-
site-directed mutagenesis, the mutation occurs naturally in humans altering the tetrahydrobiopterin responsiveness, the mutant shows reduced activity and dimer stability compared to the wild-type
R243Q
exon 7 G728A mutation naturally occuring in phenylketonuria patient from the Cukurova region in Turkey, sequence determination and analysis
R243Q
-
site-directed mutagenesis, the common mutation occurs naturally in phenylketonuria patients from east asia, the mutant shows reduced activity compared to the wild-type, the mutation affects hydrogen binding between the amide nitrogen of R243 and the carbonyl oxygen of Asp129
R243Q
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
R252W
-
naturally occuring missense mutation causing a severe phenylketonuria phenotype
R252W
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
R261P
-
naturally occuring missense mutation causing a mild phenylketonuria phenotype
R261P
the mutant shows about 14% activity compared to the wild type enzyme
R261Q
exon 7 G728A mutation naturally occuring in phenylketonuria patients from the Cukurova region in Turkey, sequence determination and analysis, second most found mutation within 23 patients
R261Q
naturally occuring mutation involved in hyperphenylalaninemia of heterozygous patients, sequence analysis, the heterologous mutant shows reduced activity compared to the wild-type enzyme
R261Q
-
frequent naturally occuring mutation involved in enzyme deficiency and BH4-responsive hyperphenylalaninemia and/or phenylketonuria
R261Q
-
naturally occuring missense mutation causing a severe phenylketonuria phenotype
R261Q
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
R261Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme, but the mutant can be rescued by co-expression of chaperones GroEL and GroES
R261Q
the mutant shows decreased specific activity using L-phenylalanine and S-carboxymethyl-L-cysteine as substrate compared to the wild type enzyme
R261Q
the S-oxidation of S-carboxymethyl-L-cysteine is dramatically reduced in the 5,6,7,8-tetrahydro-L-biopterin responsive mutant I65T possessing 1.2-2.0% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as substrate and expressing 23-76% of the wild type PAH activity when L-phenylalanine is used as the substrate
R261Q
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine) no difference in Km (L-Phe) compared to wild-type
R261Q
-
the mutation leads to 29% of wild type activity and moderate phenyletonuria
R270K
expression in the presence of the chemical chaperone glycerol enhances activity after purification
R270K
naturally occuring mutation involved in hyperphenylalaninemia of heterozygous patients, sequence analysis, the heterologous mutant shows reduced activity compared to the wild-type enzyme
R270K
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme, but the mutant can be rescued by co-expression of chaperones GroEL and GroES
R270K
the mutant shows about 15% activity compared to the wild type enzyme
R408Q
-
site-directed mutagenesis, the mutation occurs naturally in humans altering the tetrahydrobiopterin responsiveness, the mutant shows reduced activity and dimer stability compared to the wild-type
R408W
exon 12 C1222T mutation naturally occuring in phenylketonuria patient from the Cukurova region in Turkey, sequence determination and analysis
R408W
-
naturally occuring mutation involved in hyperphenylalaninemia and/or in phenylketonuria, overview
R408W
the mutant is dysfunctional in nearly all biochemical parameters, as evidenced by disease severity in homozygous and hemizygous patients
R408W
the mutation results in the classical phenylketonuria phenotype expressing 0.2-1.8% of the wild type PAH activity when using L-phenylalanine as substrate, and has less 0.1% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as the substrate
R408W
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine or L-Phe) compared to wild-type
R408W
-
the mutant with wild type activity exhibits less than 50% of wild type protein level and leads to classic phenyletonuria
R408W/R158Q
the mutant shows 5% residual activity compared to the wild type enzyme
R408W/R158Q
the mutant shows 4% activity compared to the wild type enzyme
R413P
-
site-directed mutagenesis, the common mutation occurs naturally in phenylketonuria patients from east asia, the mutant shows reduced activity compared to the wild-type
R68S
the mutant shows decreased specific activity using L-phenylalanine and S-carboxymethyl-L-cysteine as substrate compared to the wild type enzyme
R68S
the S-oxidation of S-carboxymethyl-L-cysteine is dramatically reduced in the 5,6,7,8-tetrahydro-L-biopterin responsive mutant I65T possessing 1.2-2.0% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as substrate and expressing 23-76% of the wild type PAH activity when L-phenylalanine is used as the substrate
R68S
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine) no difference in Km (L-Phe) compared to wild-type
S349P
-
naturally occuring missense mutation causing a severe phenylketonuria phenotype
T427P
-
increase in the amount of oligomeric forms higher than tetramers after preincubation of a mixture of dimeric and tetrameric forms with phenylalanine, tetrameric form exhibits approx. 50% of wild-type tetramer phenylalanine hydroxylase activity
T427P
low basal activity, little activation by preincubation with substrate, no kinetic cooperativity
V388M
40% activity after expression in Escherichia coli in the absence of GroESL, 82% in the presence of GroESL, 78% activity after expression in COS cells at 27°C
V388M
expression in the presence of the chemical chaperone glycerol enhances activity after purification
V388M
naturally occuring mutation involved in hyperphenylalaninemia of heterozygous patients, sequence analysis, the heterologous mutant shows reduced activity compared to the wild-type enzyme
V388M
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme, but the mutant can be rescued by co-expression of chaperones GroEL and GroES
V388M
the mutant shows decreased specific activity using L-phenylalanine and S-carboxymethyl-L-cysteine as substrate compared to the wild type enzyme
V388M
the S-oxidation of S-carboxymethyl-L-cysteine is dramatically reduced in the 5,6,7,8-tetrahydro-L-biopterin responsive mutant I65T possessing 1.2-2.0% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as substrate and expressing 23-76% of the wild type PAH activity when L-phenylalanine is used as the substrate
V388M
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine or L-Phe) compared to wild-type
Y325A
-
high degree of aggregation, but suffivcient tetrameric form for characterization
Y325F
-
kinetics, thermal stability, oligomerization profile similar to wild-type
Y325F
-
stable, similar yields and oligomeric distribution as wild-type, posttranslational hydroxylation
Y414C
-
frequent naturally occuring mutation involved in enzyme deficiency and BH4-responsive hyperphenylalaninemia and/or phenylketonuria
Y414C
the mutant shows decreased specific activity using L-phenylalanine and S-carboxymethyl-L-cysteine as substrate compared to the wild type enzyme
Y414C
the S-oxidation of S-carboxymethyl-L-cysteine is dramatically reduced in the 5,6,7,8-tetrahydro-L-biopterin responsive mutant I65T possessing 1.2-2.0% of the wild type PAH activity when S-carboxymethyl-L-cysteine is used as substrate and expressing 23-76% of the wild type PAH activity when L-phenylalanine is used as the substrate
Y414C
-
heteromeric hPAH (wild-type + mutant) shows: significantly decreased Vmax values compared to wild-type, significantly increased Km values (substrate: S-carboxymethyl-L-cysteine or L-Phe) compared to wild-type
Y414C
-
the mutation leads to 1% of wild type activity and classic phenyletonuria
H264Q/V379D
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truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
H264Q/V379D
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double mutant of full length enzyme, shows significant tyrosine hydroxylation activity
H264Q/Y277H/V379D
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truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
H264Q/Y277H/V379D
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triple mutant of full length enzyme, shows significant tyrosine hydroxylation activity
R270K
-
the mutation effectively abolishes binding of L-phenylalanine in the active site and leads to strongly reduced kcat/Km value (10000 down) compared to the wild type enzyme
V379D
-
truncated enzyme containing the catalytic domain, mutant shows tyrosine hydroxylation activity
V379D
-
site-directed mutagenesis of catalytic core mutant DELTA117PheH, the isotopic effects of substrates [4-2H]-, [3,5-2H2]-, and 2H5-phenylalanine are altered compared to the wild-type enzyme, overview
additional information
gene knockdown by doublestranded RNA, significant reduction of melanization, enzyme is required for fully functional melanotic encapsulation response
additional information
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gene knockdown by doublestranded RNA, significant reduction of melanization, enzyme is required for fully functional melanotic encapsulation response
additional information
gene knockdown by doublestranded RNA, significant reduction of melanization, enzyme is required for fully functional melanotic encapsulation response
additional information
-
gene knockdown by doublestranded RNA, significant reduction of melanization, enzyme is required for fully functional melanotic encapsulation response
additional information
Q9XYQ5
gene pah-1 knockout mutant worms do not show an altered phenotype, but in combination with a second mutation of cuticle synthesis, the mutant worms lack a yellow pigment in the cuticle, and show stimulatory effect on superoxide dismutase, and severe cuticle defects, overview
additional information
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gene pah-1 knockout mutant worms do not show an altered phenotype, but in combination with a second mutation of cuticle synthesis, the mutant worms lack a yellow pigment in the cuticle, and show stimulatory effect on superoxide dismutase, and severe cuticle defects, overview
additional information
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mutant p.R68S, reduced apparent and equilibrium binding affinity for tetrahydrobiopterin, increased affinity and non-cooperative response for L-phenylalanine, strong substrate inhibition
additional information
-
N-terminal deletion of amino acid residues 1-102, reduction of Hill coefficient, square-wave pattern of surface plasmon resonance response. N-terminal deletion of amino acid residues 1-102 plus C-terminal deletion of amino acid residues 428-452, reduction of Hill coefficient, square-wave pattern of surface plasmon resonance response. C-terminal deletion of amino acid residues 428-452, surface plasmon resonance signal similar to wild-type
additional information
-
N-terminal deletion of amino acid residues 1-116, kinetics, thermal stability, oligomerization profile similar to wild-type. N-terminal deletion of amino acid residues 1-116 plus mutation Y325F, 3fold reduction in kcat-value
additional information
arginine mutations are important for the evolutionary structure and function of the phenylalanine hydroxylase gene, phenylketonuria patients from the Cukurova region in Turkey show in 50% of investigated alleles the IvsVS10-11g splicing mutation, overview
additional information
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arginine mutations are important for the evolutionary structure and function of the phenylalanine hydroxylase gene, phenylketonuria patients from the Cukurova region in Turkey show in 50% of investigated alleles the IvsVS10-11g splicing mutation, overview
additional information
identification of mutations, that alter the interaction of subunits, which could be a source of phenotypic variation in genetic diseases involving multimeric proteins, e.g. in hypephenylalaninemia, overview
additional information
-
identification of mutations, that alter the interaction of subunits, which could be a source of phenotypic variation in genetic diseases involving multimeric proteins, e.g. in hypephenylalaninemia, overview
additional information
-
identification of naturally occuring missense mutations of the PHA gene involved in phenylketonuria, an autosomal recessive metabolic disease caused by PHA deficiency, the mutants show residual or no catalytic activity
additional information
calculation and computational modeling of the probability that a mutation or an amino acid change in certain positions lead to phenylketonuria to improve clinical monitoring, diagnosis, prognosis and treatment, overview
additional information
-
determination of mutations in gene pah in patients with phenylketonuria in different Israelian populations, genotyping, genotype-phenotype correlation, overview
additional information
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determination of mutations in gene pah in patients with phenylketonuria, screening and genotyping, genotype-phenotype correlation in the different ethnic groups of Israel, responsiveness of mutants to tetrahydrobiopterin treatment, overview
additional information
-
enzyme mutation can lead to tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. BH4 responsiveness in hyperphenylalaninaemia depends on the patient's genotype and residual PAH activity, of patients with moderate and classic forms of phenylketonuria, only a few are classified as responders and the clinical significance of the effect size may be small, molecular mechanism, phenotypes and clinical treatment, overview
additional information
hyperphenylalaninemia is a group of autosomal recessive disorders caused by a wide range of PAH gene variants, identification of 5 human variants in a Southern Italian population, genotyping, overview
additional information
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hyperphenylalaninemia is a group of autosomal recessive disorders caused by a wide range of PAH gene variants, identification of 5 human variants in a Southern Italian population, genotyping, overview
additional information
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identification of 57 mutations in a wide range genotyping, the mutants show substantial residual PAH activity, average 47%, presumed to be associated with BH4-responsiveness, genotyping, genotype-phenotype correlation, overview
additional information
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identification of mutations involved in hyperphenylalaninemia and/or in phenylketonuria, genotyping of a Southern Italian population, overview
additional information
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mutations in the pah gene can lead to phenylketonuria, patients respond to treatment with tetrahydrobiopterin, the extent depends on the type of disorder, phenotypes, overview
additional information
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phenylketonuria results from a mutation in the liver enzyme phenylalanine hydroxylase, the disease is correlated with high and persistent levels of Phe in the plasma plasma of PKU patients causing permanent neurological damage. Construction of PAH-based fusion proteins with delivery moieties based on the HIV-transactivator of transcription peptide, and fragments of human hepatocyte growth factor, i.e. N-terminal and first, second, and third kringle domains, respectively, of HGF, aiming to specifically target PAH to the liver, which retain PAH activity after being internalized into liver cells, effects of the transgenic construct in HuH7, HepG2, and Colo205 cells
additional information
phenylketonuria, PKU, results from mutations in the pah gene and is characterized by elevated phenylalanine levels in the plasma, the specific category of PKU since classical PKU requires a stringent diet while milder categories may not require diet and a very important BH4-responsive category may be treated with the PAH cofactor 6R-tetrahydrobiopterin, there is a close genotype-phenotype correlation in PKU, so genotyping is very important for diagnosis and therapy, overview
additional information
-
phenylketonuria, PKU, results from mutations in the pah gene and is characterized by elevated phenylalanine levels in the plasma, the specific category of PKU since classical PKU requires a stringent diet while milder categories may not require diet and a very important BH4-responsive category may be treated with the PAH cofactor 6R-tetrahydrobiopterin, there is a close genotype-phenotype correlation in PKU, so genotyping is very important for diagnosis and therapy, overview
additional information
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construction and catalytic properties of deletion mutant DELTA117PheH, consisting of the catalytic core of the enzyme, the isotopic effects of substrates [4-2H]-, [3,5-2H2]-, and 2H5-phenylalanine are unaltered compared to the wild-type enzyme, overview
