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P00439

- PH4H_HUMAN

UniProt

P00439 - PH4H_HUMAN

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Protein

Phenylalanine-4-hydroxylase

Gene

PAH

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

Catalytic activityi

L-phenylalanine + tetrahydrobiopterin + O2 = L-tyrosine + 4a-hydroxytetrahydrobiopterin.

Cofactori

Enzyme regulationi

N-terminal region of PAH is thought to contain allosteric binding sites for phenylalanine and to constitute an "inhibitory" domain that regulates the activity of a catalytic domain in the C-terminal portion of the molecule.

Kineticsi

  1. KM=150 µM for L-Phe with BH4 as cofactor1 Publication
  2. KM=30 µM for BH41 Publication

Vmax=3640 nmol/min/mg enzyme with BH4 as cofactor (preincubated with L-Phe)1 Publication

Vmax=1230 nmol/min/mg enzyme with BH4 as cofactor (preincubated with BH4)1 Publication

Temperature dependencei

Optimum temperature is 50 degrees Celsius.1 Publication

Pathwayi

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi285 – 2851IronBy similarity
Metal bindingi290 – 2901IronBy similarity
Metal bindingi330 – 3301IronBy similarity

GO - Molecular functioni

  1. amino acid binding Source: InterPro
  2. iron ion binding Source: InterPro
  3. phenylalanine 4-monooxygenase activity Source: Reactome

GO - Biological processi

  1. catecholamine biosynthetic process Source: BHF-UCL
  2. cellular amino acid biosynthetic process Source: ProtInc
  3. cellular nitrogen compound metabolic process Source: Reactome
  4. L-phenylalanine catabolic process Source: Reactome
  5. neurotransmitter biosynthetic process Source: BHF-UCL
  6. small molecule metabolic process Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Monooxygenase, Oxidoreductase

Keywords - Biological processi

Phenylalanine catabolism

Keywords - Ligandi

Iron, Metal-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS10374-MONOMER.
BRENDAi1.14.16.1. 2681.
ReactomeiREACT_121117. Abnormal metabolism in phenylketonuria.
REACT_1786. Phenylalanine and tyrosine catabolism.
SABIO-RKP00439.
UniPathwayiUPA00139; UER00337.

Names & Taxonomyi

Protein namesi
Recommended name:
Phenylalanine-4-hydroxylase (EC:1.14.16.1)
Short name:
PAH
Alternative name(s):
Phe-4-monooxygenase
Gene namesi
Name:PAH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 12

Organism-specific databases

HGNCiHGNC:8582. PAH.

Subcellular locationi

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. extracellular vesicular exosome Source: UniProt
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Phenylketonuria (PKU) [MIM:261600]: Autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor.34 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti16 – 161S → P in PKU.
VAR_000869
Natural varianti39 – 391F → L in HPA and PKU; haplotype 1. 1 Publication
VAR_000870
Natural varianti39 – 391Missing in PKU; haplotypes 9,21. 2 Publications
VAR_000871
Natural varianti40 – 401S → L in PKU. 1 Publication
VAR_000872
Natural varianti41 – 411L → F in PKU.
VAR_000873
Natural varianti41 – 411L → P in PKU; mild.
VAR_009240
Natural varianti42 – 421K → I in PKU; haplotype 21.
VAR_000874
Natural varianti45 – 451V → A in PKU. 1 Publication
VAR_067994
Natural varianti46 – 461G → S in PKU; haplotype 5; significantly reduces phenylalanine binding. 1 Publication
VAR_000875
Natural varianti47 – 471A → V in non-PKU HPA; haplotype 4; significantly reduces phenylalanine binding. 1 Publication
VAR_000876
Natural varianti48 – 481L → S in PKU; mild; haplotypes 3,4. 5 Publications
VAR_000877
Natural varianti53 – 531R → H in PKU. 1 Publication
Corresponds to variant rs118092776 [ dbSNP | Ensembl ].
VAR_000878
Natural varianti55 – 551F → L in HPA and PKU; does not affect oligomerization; results in loss of substrate activation. 2 Publications
VAR_000879
Natural varianti56 – 561E → D in PKU; haplotype 10.
VAR_000880
Natural varianti61 – 611N → D in PKU. 1 Publication
VAR_067995
Natural varianti62 – 621L → P in PKU. 1 Publication
VAR_067996
Natural varianti63 – 642TH → PN in PKU; haplotype 1; abolishes phenylalanine binding.
VAR_000881
Natural varianti65 – 651I → N in PKU. 1 Publication
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_000882
Natural varianti65 – 651I → S in PKU; results in disturbed oligomerization; results in loss of substrate activation. 1 Publication
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_067997
Natural varianti65 – 651I → T in PKU; haplotypes 1,5,9,21,B; abolishes phenylalanine binding. 3 Publications
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_000883
Natural varianti65 – 651I → V in HPA and PKU. 2 Publications
VAR_067998
Natural varianti67 – 671S → P in PKU; haplotype 4.
VAR_000884
Natural varianti68 – 681R → S in PKU; haplotype 1; significantly reduces phenylalanine binding. 1 Publication
VAR_000885
Natural varianti76 – 761E → A in PKU.
VAR_000886
Natural varianti76 – 761E → G in non-PKU HPA. 1 Publication
VAR_067999
Natural varianti84 – 841D → Y in PKU; haplotype 4.
VAR_000887
Natural varianti87 – 871S → R in non-PKU HPA; haplotype 1. 1 Publication
VAR_000888
Natural varianti92 – 921T → I in PKU.
VAR_000889
Natural varianti94 – 941Missing in PKU; mild; haplotype 2. 1 Publication
VAR_000890
Natural varianti98 – 981L → S in non-PKU HPA.
VAR_000891
Natural varianti104 – 1041A → D in PKU; mild; haplotype 1.
VAR_000892
Natural varianti124 – 1241T → I in PKU; haplotype 28.
VAR_000893
Natural varianti129 – 1291D → Y in PKU.
VAR_000894
Natural varianti143 – 1431D → G in PKU; haplotype 11.
VAR_000895
Natural varianti145 – 1451D → V in PKU.
VAR_011566
Natural varianti146 – 1461H → Y in PKU.
VAR_000896
Natural varianti148 – 1481G → S in PKU; haplotypes 1,2,7.
VAR_000897
Natural varianti151 – 1511D → H in PKU; haplotypes 1,8.
VAR_000898
Natural varianti154 – 1541Y → N in PKU.
VAR_000899
Natural varianti155 – 1551R → P in PKU.
VAR_009242
Natural varianti157 – 1571R → N in PKU; severe; 5% activity; requires 2 nucleotide substitutions.
VAR_000900
Natural varianti157 – 1571R → S in PKU. 1 Publication
VAR_068000
Natural varianti158 – 1581R → Q in PKU; haplotypes 1,2,4,7,16, 28. 3 Publications
VAR_000901
Natural varianti158 – 1581R → W in PKU.
VAR_000902
Natural varianti160 – 1601Q → P in PKU.
VAR_000903
Natural varianti161 – 1611F → S in PKU; haplotype 4.
VAR_000904
Natural varianti164 – 1641I → T in PKU; haplotype 1. 1 Publication
VAR_000905
Natural varianti167 – 1671N → I in PKU. 1 Publication
Corresponds to variant rs77554925 [ dbSNP | Ensembl ].
VAR_000906
Natural varianti169 – 1691R → H in PKU.
VAR_011568
Natural varianti170 – 1701H → Q in PKU; does not affect oligomerization. 1 Publication
VAR_068001
Natural varianti170 – 1701H → R in PKU.
VAR_000907
Natural varianti171 – 1711G → A in PKU; haplotype 1. 1 Publication
VAR_000908
Natural varianti171 – 1711G → R in PKU.
VAR_000909
Natural varianti173 – 1731P → T in PKU; haplotype 4.
VAR_000910
Natural varianti174 – 1741I → T in PKU; haplotype 1.
VAR_000911
Natural varianti174 – 1741I → V in PKU.
VAR_011570
Natural varianti175 – 1751P → A in PKU.
VAR_000912
Natural varianti176 – 1761R → L in non-PKU HPA. 1 Publication
VAR_000913
Natural varianti176 – 1761R → P in PKU.
VAR_000914
Natural varianti177 – 1771V → L in PKU; haplotype 6. 1 Publication
VAR_000915
Natural varianti178 – 1781E → G in non-PKU HPA. 1 Publication
VAR_000916
Natural varianti183 – 1831E → Q in PKU.
VAR_009243
Natural varianti190 – 1901V → A in PKU; haplotype 3. 2 Publications
VAR_000917
Natural varianti194 – 1941L → P in PKU.
VAR_000918
Natural varianti194 – 1941Missing in PKU.
VAR_000919
Natural varianti197 – 1971Missing in PKU.
VAR_000920
Natural varianti198 – 1981Missing in PKU; haplotype 2.
VAR_000921
Natural varianti201 – 2011H → R in PKU.
VAR_000922
Natural varianti201 – 2011H → Y in non-PKU HPA; haplotype 1. 2 Publications
VAR_000923
Natural varianti204 – 2041Y → C in PKU; mild; haplotypes 3,4. 1 Publication
VAR_000924
Natural varianti205 – 2051E → A in PKU.
VAR_011571
Natural varianti206 – 2061Y → D in PKU.
VAR_000925
Natural varianti207 – 2071N → D in PKU. 1 Publication
VAR_000926
Natural varianti207 – 2071N → S in PKU; severe; haplotype 4. 1 Publication
VAR_000927
Natural varianti211 – 2111P → T in PKU; haplotype 4.
VAR_000928
Natural varianti212 – 2121L → P in PKU.
VAR_000929
Natural varianti213 – 2131L → P in PKU; severe. 1 Publication
VAR_000930
Natural varianti217 – 2171C → G in PKU.
VAR_000931
Natural varianti218 – 2181G → V in PKU; haplotypes 1,2.
VAR_000932
Natural varianti221 – 2211E → G in PKU; haplotype 4. 1 Publication
VAR_000933
Natural varianti222 – 2221D → V in PKU; haplotypes 3,4.
VAR_000934
Natural varianti224 – 2241I → M in PKU; haplotype 4.
VAR_000935
Natural varianti225 – 2251P → R in PKU.
VAR_000936
Natural varianti225 – 2251P → T in PKU; haplotype 1.
VAR_000937
Natural varianti226 – 2261Q → H in PKU. 1 Publication
VAR_068003
Natural varianti230 – 2301V → I in non-PKU HPA; haplotype 4. 1 Publication
VAR_000938
Natural varianti231 – 2311S → F in PKU.
VAR_009244
Natural varianti231 – 2311S → P in PKU.
VAR_000939
Natural varianti233 – 2331F → L in PKU; haplotypes 2,3.
VAR_000940
Natural varianti238 – 2381T → P in PKU; haplotype 4.
VAR_000941
Natural varianti239 – 2391G → S in PKU. 1 Publication
VAR_000942
Natural varianti240 – 2401F → S in PKU.
VAR_011572
Natural varianti241 – 2411R → C in non-PKU HPA and PKU; haplotype 34. 3 Publications
VAR_000943
Natural varianti241 – 2411R → H in PKU; haplotypes 1,5.
VAR_000944
Natural varianti241 – 2411R → L in PKU.
VAR_000945
Natural varianti242 – 2421L → F in PKU.
VAR_000946
Natural varianti243 – 2431R → Q in non-PKU HPA and PKU; haplotypes 4,7,9. 2 Publications
VAR_000947
Natural varianti244 – 2441P → L in PKU; haplotype 12. 1 Publication
VAR_000948
Natural varianti245 – 2451V → A in PKU, HPA and non-PKU HPA; haplotypes 3,7. 4 Publications
VAR_000949
Natural varianti245 – 2451V → E in PKU; haplotype 11.
VAR_000950
Natural varianti245 – 2451V → L in PKU.
VAR_000951
Natural varianti246 – 2461A → D in PKU.
VAR_000952
Natural varianti247 – 2471G → V in PKU; haplotype 4.
VAR_000953
Natural varianti248 – 2481L → P in PKU.
VAR_000954
Natural varianti249 – 2491L → F in PKU; haplotype 1.
VAR_000955
Natural varianti252 – 2521R → G in PKU; haplotype 7.
VAR_000956
Natural varianti252 – 2521R → Q in PKU; haplotype 1. 1 Publication
VAR_000957
Natural varianti252 – 2521R → W in PKU; haplotypes 1,6,7,8,42, 69; complete loss of activity. 4 Publications
VAR_000958
Natural varianti255 – 2551L → S in PKU; haplotype 36. 1 Publication
VAR_000960
Natural varianti255 – 2551L → V in PKU; haplotypes 18,21.
VAR_000959
Natural varianti257 – 2571G → C in PKU.
VAR_000961
Natural varianti259 – 2591A → T in PKU; haplotype 3.
VAR_000962
Natural varianti259 – 2591A → V in PKU; haplotypes 7,42.
VAR_000963
Natural varianti261 – 2611R → P in PKU.
VAR_000964
Natural varianti261 – 2611R → Q in HPA and PKU; mild; haplotypes 1,2,4,22, 24,28. 5 Publications
Corresponds to variant rs5030849 [ dbSNP | Ensembl ].
VAR_000965
Natural varianti263 – 2631F → L in PKU.
VAR_000966
Natural varianti264 – 2641H → L in PKU.
VAR_000967
Natural varianti265 – 2651C → G in PKU.
VAR_000968
Natural varianti269 – 2691I → L in non-PKU HPA. 1 Publication
VAR_000969
Natural varianti270 – 2701R → K in PKU.
VAR_000970
Natural varianti270 – 2701R → S in PKU; haplotype 1.
VAR_000971
Natural varianti271 – 2711H → Y in PKU.
VAR_000972
Natural varianti273 – 2731S → F in PKU; haplotype 7.
VAR_000973
Natural varianti275 – 2751P → L in PKU; reduced activity; increased affinity for the substrate; mildly reduced substrate activation; decreased cofactor affinity. 1 Publication
VAR_068004
Natural varianti276 – 2761M → I in PKU.
VAR_000974
Natural varianti276 – 2761M → V in PKU; haplotype 4. 1 Publication
VAR_000975
Natural varianti277 – 2771Y → C in PKU.
VAR_000976
Natural varianti277 – 2771Y → D in PKU; haplotype 2.
VAR_000977
Natural varianti278 – 2781T → A in PKU.
VAR_000978
Natural varianti278 – 2781T → N in PKU.
VAR_000979
Natural varianti280 – 2801E → K in PKU; haplotypes 1,2,4,16,38; partial residual activity. 3 Publications
VAR_000980
Natural varianti281 – 2811P → L in PKU; haplotypes 1,4. 5 Publications
VAR_000981
Natural varianti282 – 2821D → N in PKU; haplotype 1.
VAR_000982
Natural varianti283 – 2831I → F in PKU; haplotype 21.
VAR_000983
Natural varianti283 – 2831I → N in PKU; severe. 1 Publication
VAR_000984
Natural varianti290 – 2901H → Y in PKU. 1 Publication
VAR_067758
Natural varianti297 – 2971R → C in PKU; haplotype 4.
VAR_000985
Natural varianti297 – 2971R → H in PKU.
VAR_000986
Natural varianti299 – 2991F → C in PKU; haplotype 8. 1 Publication
VAR_000987
Natural varianti300 – 3001A → S in PKU and HPA; haplotype 1; does not affect oligomerization; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 3 Publications
VAR_000988
Natural varianti300 – 3001A → V in PKU.
VAR_000989
Natural varianti303 – 3031S → P in PKU; haplotype 5.
VAR_000990
Natural varianti304 – 3041Q → R in PKU.
VAR_000991
Natural varianti306 – 3061I → V in non-PKU HPA; haplotype 4. 2 Publications
VAR_000992
Natural varianti309 – 3091A → D in PKU; haplotype 7.
VAR_000993
Natural varianti309 – 3091A → V in PKU.
VAR_000994
Natural varianti310 – 3101S → F in PKU; haplotype 7.
VAR_000995
Natural varianti311 – 3111L → P in PKU; haplotypes 1,7,10. 2 Publications
VAR_000996
Natural varianti314 – 3141P → H in PKU.
VAR_000997
Natural varianti318 – 3181I → T in PKU; partial loss of activity. 1 Publication
VAR_011574
Natural varianti322 – 3221A → G in PKU; haplotype 12.
VAR_000998
Natural varianti322 – 3221A → T in PKU; haplotype 1.
VAR_000999
Natural varianti322 – 3221A → V in PKU. 1 Publication
VAR_067759
Natural varianti325 – 3251Y → C in PKU.
VAR_009245
Natural varianti330 – 3301E → D in PKU.
VAR_009246
Natural varianti331 – 3311F → L in PKU; haplotype 1. 1 Publication
VAR_001000
Natural varianti333 – 3331L → F in PKU.
VAR_001001
Natural varianti334 – 3341C → S in PKU.
VAR_001002
Natural varianti337 – 3371G → V in PKU.
VAR_001003
Natural varianti338 – 3381D → Y in PKU; haplotype 4.
VAR_001004
Natural varianti341 – 3411K → R in PKU.
VAR_001005
Natural varianti341 – 3411K → T in PKU.
VAR_001006
Natural varianti342 – 3421A → T in PKU; haplotype 5.
VAR_001007
Natural varianti343 – 3431Y → C in PKU.
VAR_001008
Natural varianti344 – 3441G → R in PKU.
VAR_009247
Natural varianti344 – 3441G → V in PKU.
VAR_009248
Natural varianti345 – 3451A → S in PKU.
VAR_001009
Natural varianti345 – 3451A → T in PKU; haplotype 7.
VAR_001010
Natural varianti347 – 3471L → F in PKU.
VAR_001011
Natural varianti348 – 3481L → V in PKU; mild haplotype 9.
VAR_001012
Natural varianti349 – 3491S → L in PKU; severe. 1 Publication
VAR_001013
Natural varianti349 – 3491S → P in PKU; haplotypes 1,4. 1 Publication
VAR_001014
Natural varianti350 – 3501S → T in PKU; haplotype 2.
VAR_001015
Natural varianti357 – 3571C → G in PKU.
VAR_011575
Natural varianti362 – 3621P → T in PKU. 1 Publication
VAR_001016
Natural varianti364 – 3685Missing in PKU. 1 Publication
VAR_001018
Natural varianti364 – 3641Missing in PKU; haplotype 5. 1 Publication
VAR_001017
Natural varianti366 – 3661P → H in PKU.
VAR_001019
Natural varianti372 – 3721T → S in PKU.
VAR_001020
Natural varianti377 – 3771Y → C in PKU; haplotype 4.
VAR_001021
Natural varianti380 – 3801T → M in non-PKU HPA; haplotype 4. 1 Publication
VAR_001022
Natural varianti386 – 3861Y → C in PKU; common mutation.
VAR_001023
Natural varianti387 – 3871Y → H in PKU; haplotype 1.
VAR_001024
Natural varianti388 – 3881V → L in PKU. 1 Publication
VAR_001025
Natural varianti388 – 3881V → M in PKU; haplotypes 1,4.
VAR_001026
Natural varianti390 – 3901E → G in PKU and non-PKU HPA; haplotype 4. 5 Publications
VAR_001027
Natural varianti394 – 3941D → A in PKU.
VAR_001028
Natural varianti394 – 3941D → H in PKU. 1 Publication
VAR_001029
Natural varianti395 – 3951A → G in PKU.
VAR_001030
Natural varianti395 – 3951A → P in PKU; haplotype 1.
VAR_001031
Natural varianti399 – 4002Missing in PKU; haplotype 7.
VAR_001032
Natural varianti403 – 4031A → V in non-PKU HPA and PKU; haplotype 43. 4 Publications
Corresponds to variant rs5030857 [ dbSNP | Ensembl ].
VAR_001033
Natural varianti407 – 4071P → L in PKU. 1 Publication
VAR_068007
Natural varianti407 – 4071P → S in PKU.
VAR_011576
Natural varianti408 – 4081R → Q in PKU; haplotypes 4,12. 1 Publication
VAR_001034
Natural varianti408 – 4081R → W in HPA and PKU; haplotypes 1,2,4,5,13,34, 41,44; most common mutation; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 7 Publications
Corresponds to variant rs5030858 [ dbSNP | Ensembl ].
VAR_001035
Natural varianti410 – 4101F → S in PKU; mild.
VAR_009249
Natural varianti413 – 4131R → P in non-PKU HPA and PKU; haplotype 4. 2 Publications
VAR_001036
Natural varianti413 – 4131R → S in PKU; haplotype 1.
VAR_001037
Natural varianti414 – 4141Y → C in HPA and PKU; haplotype 4; does not affect oligomerization; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 2 Publications
VAR_001038
Natural varianti415 – 4151D → N in PKU, HPA and non-PKU HPA; haplotype 1. 3 Publications
VAR_001039
Natural varianti417 – 4171Y → H in PKU; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 1 Publication
VAR_068008
Natural varianti418 – 4181T → P in PKU; haplotype 4.
VAR_001040
Natural varianti421 – 4211I → S in PKU. 1 Publication
VAR_067760
Natural varianti430 – 4301L → P in PKU.
VAR_001041
Natural varianti447 – 4471A → D in PKU.
VAR_001042
Non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600]: Mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one.
Note: The disease is caused by mutations affecting the gene represented in this entry.
Hyperphenylalaninemia (HPA) [MIM:261600]: Mildest form of phenylalanine hydroxylase deficiency.9 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti20 – 201Q → L in HPA.
VAR_009239
Natural varianti39 – 391F → L in HPA and PKU; haplotype 1. 1 Publication
VAR_000870
Natural varianti47 – 471A → V in non-PKU HPA; haplotype 4; significantly reduces phenylalanine binding. 1 Publication
VAR_000876
Natural varianti55 – 551F → L in HPA and PKU; does not affect oligomerization; results in loss of substrate activation. 2 Publications
VAR_000879
Natural varianti65 – 651I → V in HPA and PKU. 2 Publications
VAR_067998
Natural varianti76 – 761E → G in non-PKU HPA. 1 Publication
VAR_067999
Natural varianti87 – 871S → R in non-PKU HPA; haplotype 1. 1 Publication
VAR_000888
Natural varianti98 – 981L → S in non-PKU HPA.
VAR_000891
Natural varianti110 – 1101S → C in HPA.
VAR_009241
Natural varianti121 – 1211F → L in HPA. 1 Publication
VAR_069776
Natural varianti167 – 1671N → S in HPA.
Corresponds to variant rs77554925 [ dbSNP | Ensembl ].
VAR_011567
Natural varianti170 – 1701H → D in HPA.
VAR_011569
Natural varianti176 – 1761R → L in non-PKU HPA. 1 Publication
VAR_000913
Natural varianti177 – 1771V → M in HPA. 1 Publication
VAR_068002
Natural varianti178 – 1781E → G in non-PKU HPA. 1 Publication
VAR_000916
Natural varianti196 – 1961S → Y in HPA. 1 Publication
VAR_069777
Natural varianti201 – 2011H → Y in non-PKU HPA; haplotype 1. 2 Publications
VAR_000923
Natural varianti230 – 2301V → I in non-PKU HPA; haplotype 4. 1 Publication
VAR_000938
Natural varianti241 – 2411R → C in non-PKU HPA and PKU; haplotype 34. 3 Publications
VAR_000943
Natural varianti243 – 2431R → Q in non-PKU HPA and PKU; haplotypes 4,7,9. 2 Publications
VAR_000947
Natural varianti245 – 2451V → A in PKU, HPA and non-PKU HPA; haplotypes 3,7. 4 Publications
VAR_000949
Natural varianti261 – 2611R → Q in HPA and PKU; mild; haplotypes 1,2,4,22, 24,28. 5 Publications
Corresponds to variant rs5030849 [ dbSNP | Ensembl ].
VAR_000965
Natural varianti269 – 2691I → L in non-PKU HPA. 1 Publication
VAR_000969
Natural varianti300 – 3001A → S in PKU and HPA; haplotype 1; does not affect oligomerization; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 3 Publications
VAR_000988
Natural varianti306 – 3061I → V in non-PKU HPA; haplotype 4. 2 Publications
VAR_000992
Natural varianti310 – 3101S → Y in HPA; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 1 Publication
VAR_068005
Natural varianti314 – 3141P → S in HPA; does not affect oligomerization; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 1 Publication
VAR_068006
Natural varianti380 – 3801T → M in non-PKU HPA; haplotype 4. 1 Publication
VAR_001022
Natural varianti390 – 3901E → G in PKU and non-PKU HPA; haplotype 4. 5 Publications
VAR_001027
Natural varianti403 – 4031A → V in non-PKU HPA and PKU; haplotype 43. 4 Publications
Corresponds to variant rs5030857 [ dbSNP | Ensembl ].
VAR_001033
Natural varianti408 – 4081R → W in HPA and PKU; haplotypes 1,2,4,5,13,34, 41,44; most common mutation; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 7 Publications
Corresponds to variant rs5030858 [ dbSNP | Ensembl ].
VAR_001035
Natural varianti413 – 4131R → P in non-PKU HPA and PKU; haplotype 4. 2 Publications
VAR_001036
Natural varianti414 – 4141Y → C in HPA and PKU; haplotype 4; does not affect oligomerization; reduction in activity is probably due to a global conformational change in the protein that reduces allostery. 2 Publications
VAR_001038
Natural varianti415 – 4151D → N in PKU, HPA and non-PKU HPA; haplotype 1. 3 Publications
VAR_001039

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi283 – 2831I → C: Loss of positive cooperativity and reduction of fold-activation by L-Phe preincubation. 1 Publication

Keywords - Diseasei

Disease mutation, Phenylketonuria

Organism-specific databases

MIMi261600. phenotype.
Orphaneti79254. Classical phenylketonuria.
2209. Maternal hyperphenylalaninemia.
79651. Mild hyperphenylalaninemia.
79253. Mild phenylketonuria.
293284. Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria.
PharmGKBiPA32911.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 452451Phenylalanine-4-hydroxylasePRO_0000205548Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei16 – 161Phosphoserine; by PKA1 Publication

Post-translational modificationi

Phosphorylation at Ser-16 increases basal activity and facilitates activation by the substrate phenylalanine.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP00439.
PaxDbiP00439.
PRIDEiP00439.

2D gel databases

UCD-2DPAGEP00439.

PTM databases

PhosphoSiteiP00439.

Expressioni

Gene expression databases

BgeeiP00439.
CleanExiHS_PAH.
ExpressionAtlasiP00439. baseline and differential.
GenevestigatoriP00439.

Organism-specific databases

HPAiHPA028407.
HPA031642.

Interactioni

Subunit structurei

Homodimer and homotetramer.1 Publication

Protein-protein interaction databases

BioGridi111090. 4 interactions.
DIPiDIP-58927N.
IntActiP00439. 3 interactions.
STRINGi9606.ENSP00000303500.

Structurei

Secondary structure

1
452
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi125 – 1339Combined sources
Beta strandi135 – 1384Combined sources
Helixi140 – 1423Combined sources
Turni147 – 1504Combined sources
Helixi152 – 16716Combined sources
Helixi181 – 20121Combined sources
Helixi204 – 21714Combined sources
Helixi227 – 23812Combined sources
Beta strandi241 – 2444Combined sources
Beta strandi246 – 2483Combined sources
Helixi251 – 2599Combined sources
Beta strandi262 – 2654Combined sources
Helixi283 – 2897Combined sources
Helixi291 – 2944Combined sources
Helixi297 – 31014Combined sources
Helixi315 – 32713Combined sources
Turni328 – 3314Combined sources
Beta strandi333 – 3364Combined sources
Beta strandi339 – 3424Combined sources
Helixi345 – 3484Combined sources
Helixi351 – 3577Combined sources
Beta strandi359 – 3668Combined sources
Helixi369 – 3724Combined sources
Beta strandi379 – 3813Combined sources
Beta strandi384 – 3907Combined sources
Helixi392 – 40312Combined sources
Beta strandi409 – 4157Combined sources
Turni416 – 4194Combined sources
Beta strandi420 – 4245Combined sources
Helixi426 – 45025Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1DMWX-ray2.00A118-424[»]
1J8TX-ray1.70A103-427[»]
1J8UX-ray1.50A103-427[»]
1KW0X-ray2.50A103-427[»]
1LRMX-ray2.10A103-427[»]
1MMKX-ray2.00A103-427[»]
1MMTX-ray2.00A103-427[»]
1PAHX-ray2.00A117-424[»]
1TDWX-ray2.10A117-424[»]
1TG2X-ray2.20A117-424[»]
2PAHX-ray3.10A/B118-452[»]
3PAHX-ray2.00A117-424[»]
4ANPX-ray2.11A104-427[»]
4PAHX-ray2.00A117-424[»]
5PAHX-ray2.10A117-424[»]
6PAHX-ray2.15A117-424[»]
ProteinModelPortaliP00439.
SMRiP00439. Positions 19-452.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP00439.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini36 – 11479ACTPROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 ACT domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG3186.
GeneTreeiENSGT00390000010268.
HOGENOMiHOG000233373.
HOVERGENiHBG006841.
InParanoidiP00439.
KOiK00500.
OMAiRYNAYTQ.
OrthoDBiEOG7KM5T1.
PhylomeDBiP00439.
TreeFamiTF313327.

Family and domain databases

Gene3Di1.10.800.10. 1 hit.
InterProiIPR002912. ACT_dom.
IPR001273. ArAA_hydroxylase.
IPR018301. ArAA_hydroxylase_Fe/CU_BS.
IPR019774. Aromatic-AA_hydroxylase_C.
IPR005961. Phe-4-hydroxylase_tetra.
IPR019773. Tyrosine_3-monooxygenase-like.
[Graphical view]
PANTHERiPTHR11473. PTHR11473. 1 hit.
PfamiPF01842. ACT. 1 hit.
PF00351. Biopterin_H. 1 hit.
[Graphical view]
PIRSFiPIRSF000336. TH. 1 hit.
PRINTSiPR00372. FYWHYDRXLASE.
SUPFAMiSSF56534. SSF56534. 1 hit.
TIGRFAMsiTIGR01268. Phe4hydrox_tetr. 1 hit.
PROSITEiPS51671. ACT. 1 hit.
PS00367. BH4_AAA_HYDROXYL_1. 1 hit.
PS51410. BH4_AAA_HYDROXYL_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P00439-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK
60 70 80 90 100
VLRLFEENDV NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH
110 120 130 140 150
DIGATVHELS RDKKKDTVPW FPRTIQELDR FANQILSYGA ELDADHPGFK
160 170 180 190 200
DPVYRARRKQ FADIAYNYRH GQPIPRVEYM EEEKKTWGTV FKTLKSLYKT
210 220 230 240 250
HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF RLRPVAGLLS
260 270 280 290 300
SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
310 320 330 340 350
QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS
360 370 380 390 400
FGELQYCLSE KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR
410 420 430 440 450
NFAATIPRPF SVRYDPYTQR IEVLDNTQQL KILADSINSE IGILCSALQK

IK
Length:452
Mass (Da):51,862
Last modified:July 21, 1986 - v1
Checksum:i018F00EBBBDDCE2F
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti183 – 1831E → G in AAH26251. (PubMed:15489334)Curated

Polymorphismi

The Glu-274 variant occurs on approximately 4% of African-American PAH alleles. The enzyme activity of the variant protein is indistinguishable from that of the wild-type form.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti16 – 161S → P in PKU.
VAR_000869
Natural varianti20 – 201Q → L in HPA.
VAR_009239
Natural varianti39 – 391F → L in HPA and PKU; haplotype 1. 1 Publication
VAR_000870
Natural varianti39 – 391Missing in PKU; haplotypes 9,21. 2 Publications
VAR_000871
Natural varianti40 – 401S → L in PKU. 1 Publication
VAR_000872
Natural varianti41 – 411L → F in PKU.
VAR_000873
Natural varianti41 – 411L → P in PKU; mild.
VAR_009240
Natural varianti42 – 421K → I in PKU; haplotype 21.
VAR_000874
Natural varianti45 – 451V → A in PKU. 1 Publication
VAR_067994
Natural varianti46 – 461G → S in PKU; haplotype 5; significantly reduces phenylalanine binding. 1 Publication
VAR_000875
Natural varianti47 – 471A → V in non-PKU HPA; haplotype 4; significantly reduces phenylalanine binding. 1 Publication
VAR_000876
Natural varianti48 – 481L → S in PKU; mild; haplotypes 3,4. 5 Publications
VAR_000877
Natural varianti53 – 531R → H in PKU. 1 Publication
Corresponds to variant rs118092776 [ dbSNP | Ensembl ].
VAR_000878
Natural varianti55 – 551F → L in HPA and PKU; does not affect oligomerization; results in loss of substrate activation. 2 Publications
VAR_000879
Natural varianti56 – 561E → D in PKU; haplotype 10.
VAR_000880
Natural varianti61 – 611N → D in PKU. 1 Publication
VAR_067995
Natural varianti62 – 621L → P in PKU. 1 Publication
VAR_067996
Natural varianti63 – 642TH → PN in PKU; haplotype 1; abolishes phenylalanine binding.
VAR_000881
Natural varianti65 – 651I → N in PKU. 1 Publication
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_000882
Natural varianti65 – 651I → S in PKU; results in disturbed oligomerization; results in loss of substrate activation. 1 Publication
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_067997
Natural varianti65 – 651I → T in PKU; haplotypes 1,5,9,21,B; abolishes phenylalanine binding. 3 Publications
Corresponds to variant rs75193786 [ dbSNP | Ensembl ].
VAR_000883
Natural varianti65 – 651I → V in HPA and PKU. 2 Publications
VAR_067998
Natural varianti67 – 671S → P in PKU; haplotype 4.
VAR_000884
Natural varianti68 – 681R → S in PKU; haplotype 1; significantly reduces phenylalanine binding. 1 Publication
VAR_000885
Natural varianti76 – 761E → A in PKU.
VAR_000886
Natural varianti76 – 761E → G in non-PKU HPA. 1 Publication
VAR_067999
Natural varianti84 – 841D → Y in PKU; haplotype 4.
VAR_000887
Natural varianti87 – 871S → R in non-PKU HPA; haplotype 1. 1 Publication
VAR_000888
Natural varianti92 – 921T → I in PKU.
VAR_000889
Natural varianti94 – 941Missing in PKU; mild; haplotype 2. 1 Publication
VAR_000890
Natural varianti98 – 981L → S in non-PKU HPA.
VAR_000891
Natural varianti104 – 1041A → D in PKU; mild; haplotype 1.
VAR_000892
Natural varianti110 – 1101S → C in HPA.
VAR_009241
Natural varianti121 – 1211F → L in HPA. 1 Publication
VAR_069776
Natural varianti124 – 1241T → I in PKU; haplotype 28.
VAR_000893
Natural varianti129 – 1291D → Y in PKU.
VAR_000894
Natural varianti143 – 1431D → G in PKU; haplotype 11.
VAR_000895
Natural varianti145 – 1451D → V in PKU.
VAR_011566
Natural varianti146 – 1461H → Y in PKU.
VAR_000896
Natural varianti148 – 1481G → S in PKU; haplotypes 1,2,7.
VAR_000897
Natural varianti151 – 1511D → H in PKU; haplotypes 1,8.
VAR_000898
Natural varianti154 – 1541Y → N in PKU.
VAR_000899
Natural varianti155 – 1551R → P in PKU.
VAR_009242
Natural varianti157 – 1571R → N in PKU; severe; 5% activity; requires 2 nucleotide substitutions.
VAR_000900
Natural varianti157 – 1571R → S in PKU. 1 Publication
VAR_068000
Natural varianti158 – 1581R → Q in PKU; haplotypes 1,2,4,7,16, 28. 3 Publications
VAR_000901
Natural varianti158 – 1581R → W in PKU.
VAR_000902
Natural varianti160 – 1601Q → P in PKU.
VAR_000903
Natural varianti161 – 1611F → S in PKU; haplotype 4.
VAR_000904
Natural varianti164 – 1641I → T in PKU; haplotype 1. 1 Publication
VAR_000905
Natural varianti167 – 1671N → I in PKU. 1 Publication
Corresponds to variant rs77554925 [ dbSNP | Ensembl ].
VAR_000906
Natural varianti167 – 1671N → S in HPA.
Corresponds to variant rs77554925 [ dbSNP | Ensembl ].
VAR_011567
Natural varianti169 – 1691R → H in PKU.
VAR_011568
Natural varianti170 – 1701H → D in HPA.
VAR_011569
Natural varianti170 – 1701H → Q in PKU; does not affect oligomerization. 1 Publication
VAR_068001
Natural varianti170 – 1701H → R in PKU.
VAR_000907
Natural varianti171 – 1711G → A in PKU; haplotype 1. 1 Publication
VAR_000908
Natural varianti171 – 1711G → R in PKU.
VAR_000909
Natural varianti173 – 1731P → T in PKU; haplotype 4.
VAR_000910
Natural varianti174 – 1741I → T in PKU; haplotype 1.
VAR_000911
Natural varianti174 – 1741I → V in PKU.
VAR_011570
Natural varianti175 – 1751P → A in PKU.
VAR_000912
Natural varianti176 – 1761R → L in non-PKU HPA. 1 Publication
VAR_000913
Natural varianti176 – 1761R → P in PKU.
VAR_000914
Natural varianti177 – 1771V → L in PKU; haplotype 6. 1 Publication
VAR_000915
Natural varianti177 – 1771V → M in HPA. 1 Publication
VAR_068002
Natural varianti178 – 1781E → G in non-PKU HPA. 1 Publication
VAR_000916
Natural varianti183 – 1831E → Q in PKU.
VAR_009243
Natural varianti190 – 1901V → A in PKU; haplotype 3. 2 Publications
VAR_000917
Natural varianti194 – 1941L → P in PKU.
VAR_000918
Natural varianti194 – 1941Missing in PKU.
VAR_000919
Natural varianti196 – 1961S → Y in HPA. 1 Publication