Reviewed, UniProtKB/Swiss-Prot P00439 (PH4H_HUMAN)

Names and origin

Protein names

Recommended name:
    Phenylalanine-4-hydroxylase
      Short name=PAH
    EC=1.14.16.1
Alternative name(s):
    Phe-4-monooxygenase

Gene names

Name:

PAH

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	452 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	L-phenylalanine + tetrahydrobiopterin + O2 = L-tyrosine + 4a-hydroxytetrahydrobiopterin.
Cofactor	Fe2+ ion.
Enzyme regulation	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.
Pathway	Amino-acid degradation; L-phenylalanine degradation; acetoacetic acid and fumarate from L-phenylalanine: step 1/6.
Subunit structure	Homodimer.
Polymorphism	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.
Involvement in disease	Defects in PAH are the cause of phenylketonuria (PKU) [MIM:261600]. PKU is an 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. Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.25 Ref.26 Ref.27 Ref.28 Ref.30 Ref.32 Ref.33 Ref.34 Ref.35 Ref.36 Ref.38 Ref.39 Ref.40 Ref.41 Ref.42 Ref.43 Ref.44 Ref.46 Ref.47 Ref.48 Ref.49 Ref.50 Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600]. Non-PKU HPA is a 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. Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600]. HPA is the mildest form of phenylalanine hydroxylase deficiency. Ref.49 Ref.24 Ref.29 Ref.31 Ref.45
Sequence similarities	Belongs to the biopterin-dependent aromatic amino acid hydroxylase family. Contains 1 ACT domain.

Ontologies

Keywords
Biological process	Phenylalanine catabolism
Coding sequence diversity	Polymorphism
Disease	Disease mutation Phenylketonuria
Ligand	Iron Metal-binding
Molecular function	Monooxygenase Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	L-phenylalanine catabolic process Inferred from electronic annotation. Source: UniProtKB-KW catecholamine biosynthetic process Non-traceable author statement. Source: UniProtKB neurotransmitter biosynthetic process Non-traceable author statement. Source: UniProtKB oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	amino acid binding Inferred from electronic annotation. Source: InterPro iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW phenylalanine 4-monooxygenase activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 452

452

Phenylalanine-4-hydroxylase

PRO_0000205548

Regions

Domain

35 – 110

76

ACT

Sites

Metal binding

285

1

Iron By similarity

Metal binding

290

1

Iron By similarity

Metal binding

330

1

Iron By similarity

Amino acid modifications

Modified residue

16

1

Phosphoserine; by PKA By similarity

Natural variations

Natural variant

16

1

S → P in PKU.

VAR_000869

Natural variant

20

1

Q → L in HPA.

VAR_009239

Natural variant

39

1

F → L in PKU; haplotype 1. Ref.42

VAR_000870

Natural variant

39

1

Missing in PKU; haplotypes 9,21. Ref.42

VAR_000871

Natural variant

40

1

S → L in PKU. Ref.34

VAR_000872

Natural variant

41

1

L → F in PKU.

VAR_000873

Natural variant

41

1

L → P in PKU; mild.

VAR_009240

Natural variant

42

1

K → I in PKU; haplotype 21.

VAR_000874

Natural variant

46

1

G → S in PKU; haplotype 5; significantly reduces phenylalanine binding. Ref.34

VAR_000875

Natural variant

47

1

A → V in non-PKU HPA; haplotype 4; significantly reduces phenylalanine binding. Ref.31

VAR_000876

Natural variant

48

1

L → S in PKU; mild; haplotypes 3,4. Ref.22 Ref.34

VAR_000877

Natural variant

53

1

R → H in PKU. Ref.41

VAR_000878

Natural variant

55

1

F → L in PKU.

VAR_000879

Natural variant

56

1

E → D in PKU; haplotype 10.

VAR_000880

Natural variant

63 – 64

2

TH → PN in PKU; haplotype 1; abolishes phenylalanine binding.

VAR_000881

Natural variant

65

1

I → N in PKU. Ref.34 Ref.42

VAR_000882

Natural variant

65

1

I → T in PKU; haplotypes 1,5,9,21,B; abolishes phenylalanine binding. Ref.34 Ref.42

VAR_000883

Natural variant

67

1

S → P in PKU; haplotype 4.

VAR_000884

Natural variant

68

1

R → S in PKU; haplotype 1; significantly reduces phenylalanine binding. Ref.34

VAR_000885

Natural variant

76

1

E → A in PKU.

VAR_000886

Natural variant

84

1

D → Y in PKU; haplotype 4.

VAR_000887

Natural variant

87

1

S → R in non-PKU HPA; haplotype 1. Ref.31

VAR_000888

Natural variant

92

1

T → I in PKU.

VAR_000889

Natural variant

94

1

Missing in PKU; mild; haplotype 2. Ref.23

VAR_000890

Natural variant

98

1

L → S in non-PKU HPA.

VAR_000891

Natural variant

104

1

A → D in PKU; mild; haplotype 1. Ref.44

VAR_000892

Natural variant

110

1

S → C in HPA.

VAR_009241

Natural variant

124

1

T → I in PKU; haplotype 28.

VAR_000893

Natural variant

129

1

D → Y in PKU.

VAR_000894

Natural variant

143

1

D → G in PKU; haplotype 11. Ref.33

VAR_000895

Natural variant

145

1

D → V in PKU.

VAR_011566

Natural variant

146

1

H → Y in PKU.

VAR_000896

Natural variant

148

1

G → S in PKU; haplotypes 1,2,7.

VAR_000897

Natural variant

151

1

D → H in PKU; haplotypes 1,8.

VAR_000898

Natural variant

154

1

Y → N in PKU.

VAR_000899

Natural variant

155

1

R → P in PKU.

VAR_009242

Natural variant

157

1

R → N in PKU; severe; 5% activity; requires 2 nucleotide substitutions. Ref.44

VAR_000900

Natural variant

158

1

R → Q in PKU; haplotypes 1,2,4,7,16, 28. Ref.42

VAR_000901

Natural variant

158

1

R → W in PKU. Ref.42

VAR_000902

Natural variant

160

1

Q → P in PKU.

VAR_000903

Natural variant

161

1

F → S in PKU; haplotype 4.

VAR_000904

Natural variant

164

1

I → T in PKU; haplotype 1. Ref.32

VAR_000905

Natural variant

167

1

N → I in PKU. Ref.42

VAR_000906

Natural variant

167

1

N → S in HPA.

VAR_011567

Natural variant

169

1

R → H in PKU.

VAR_011568

Natural variant

170

1

H → D in HPA.

VAR_011569

Natural variant

170

1

H → R in PKU.

VAR_000907

Natural variant

171

1

G → A in PKU; haplotype 1. Ref.32

VAR_000908

Natural variant

171

1

G → R in PKU. Ref.32

VAR_000909

Natural variant

173

1

P → T in PKU; haplotype 4.

VAR_000910

Natural variant

174

1

I → T in PKU; haplotype 1.

VAR_000911

Natural variant

174

1

I → V in PKU.

VAR_011570

Natural variant

175

1

P → A in PKU.

VAR_000912

Natural variant

176

1

R → L in non-PKU HPA. Ref.31

VAR_000913

Natural variant

176

1

R → P in PKU.

VAR_000914

Natural variant

177

1

V → L in PKU; haplotype 6.

VAR_000915

Natural variant

178

1

E → G in non-PKU HPA.

VAR_000916

Natural variant

183

1

E → Q in PKU.

VAR_009243

Natural variant

190

1

V → A in PKU; haplotype 3. Ref.42

VAR_000917

Natural variant

194

1

L → P in PKU.

VAR_000918

Natural variant

194

1

Missing in PKU.

VAR_000919

Natural variant

197

1

Missing in PKU.

VAR_000920

Natural variant

198

1

Missing in PKU; haplotype 2.

VAR_000921

Natural variant

201

1

H → R in PKU.

VAR_000922

Natural variant

201

1

H → Y in non-PKU HPA; haplotype 1.

VAR_000923

Natural variant

204

1

Y → C in PKU; mild; haplotypes 3,4. Ref.35

VAR_000924

Natural variant

205

1

E → A in PKU.

VAR_011571

Natural variant

206

1

Y → D in PKU.

VAR_000925

Natural variant

207

1

N → D in PKU. Ref.35 Ref.41

VAR_000926

Natural variant

207

1

N → S in PKU; severe; haplotype 4. Ref.35 Ref.41

VAR_000927

Natural variant

211

1

P → T in PKU; haplotype 4.

VAR_000928

Natural variant

212

1

L → P in PKU.

VAR_000929

Natural variant

213

1

L → P in PKU; severe.

VAR_000930

Natural variant

217

1

C → G in PKU.

VAR_000931

Natural variant

218

1

G → V in PKU; haplotypes 1,2.

VAR_000932

Natural variant

221

1

E → G in PKU; haplotype 4. Ref.22

VAR_000933

Natural variant

222

1

D → V in PKU; haplotypes 3,4.

VAR_000934

Natural variant

224

1

I → M in PKU; haplotype 4.

VAR_000935

Natural variant

225

1

P → R in PKU.

VAR_000936

Natural variant

225

1

P → T in PKU; haplotype 1.

VAR_000937

Natural variant

230

1

V → I in non-PKU HPA; haplotype 4.

VAR_000938

Natural variant

231

1

S → F in PKU.

VAR_009244

Natural variant

231

1

S → P in PKU.

VAR_000939

Natural variant

233

1

F → L in PKU; haplotypes 2,3.

VAR_000940

Natural variant

238

1

T → P in PKU; haplotype 4.

VAR_000941

Natural variant

239

1

G → S in PKU. Ref.32

VAR_000942

Natural variant

240

1

F → S in PKU.

VAR_011572

Natural variant

241

1

R → C in non-PKU HPA and PKU; haplotype 34. Ref.34 Ref.42 Ref.45

VAR_000943

Natural variant

241

1

R → H in PKU; haplotypes 1,5. Ref.34 Ref.42

VAR_000944

Natural variant

241

1

R → L in PKU. Ref.34 Ref.42

VAR_000945

Natural variant

242

1

L → F in PKU.

VAR_000946

Natural variant

243

1

R → Q in non-PKU HPA and PKU; haplotypes 4,7,9. Ref.39 Ref.45

VAR_000947

Natural variant

244

1

P → L in PKU; haplotype 12. Ref.27

VAR_000948

Natural variant

245

1

V → A in non-PKU HPA; haplotypes 3,7. Ref.34 Ref.31

VAR_000949

Natural variant

245

1

V → E in PKU; haplotype 11. Ref.34

VAR_000950

Natural variant

245

1

V → L in PKU. Ref.34

VAR_000951

Natural variant

246

1

A → D in PKU.

VAR_000952

Natural variant

247

1

G → V in PKU; haplotype 4.

VAR_000953

Natural variant

248

1

L → P in PKU.

VAR_000954

Natural variant

249

1

L → F in PKU; haplotype 1.

VAR_000955

Natural variant

252

1

R → G in PKU; haplotype 7. Ref.20 Ref.32 Ref.50

VAR_000956

Natural variant

252

1

R → Q in PKU; haplotype 1. Ref.20 Ref.32 Ref.50

VAR_000957

Natural variant

252

1

R → W in PKU; haplotypes 1,6,7,8,42, 69; complete loss of activity. Ref.20 Ref.32 Ref.50

VAR_000958

Natural variant

255

1

L → S in PKU; haplotype 36. Ref.19

VAR_000960

Natural variant

255

1

L → V in PKU; haplotypes 18,21. Ref.19

VAR_000959

Natural variant

257

1

G → C in PKU.

VAR_000961

Natural variant

259

1

A → T in PKU; haplotype 3.

VAR_000962

Natural variant

259

1

A → V in PKU; haplotypes 7,42.

VAR_000963

Natural variant

261

1

R → P in PKU. Ref.18 Ref.34

VAR_000964

Natural variant

261

1

R → Q in PKU; mild; haplotypes 1,2,4,22, 24,28. dbSNP rs5030849. Ref.18 Ref.34

VAR_000965

Natural variant

263

1

F → L in PKU.

VAR_000966

Natural variant

264

1

H → L in PKU.

VAR_000967

Natural variant

265

1

C → G in PKU.

VAR_000968

Natural variant

269

1

I → L in non-PKU HPA.

VAR_000969

Natural variant

270

1

R → K in PKU.

VAR_000970

Natural variant

270

1

R → S in PKU; haplotype 1.

VAR_000971

Natural variant

271

1

H → Y in PKU.

VAR_000972

Natural variant

273

1

S → F in PKU; haplotype 7.

VAR_000973

Natural variant

274

1

K → E Ref.50

VAR_011573

Natural variant

276

1

M → I in PKU. Ref.30

VAR_000974

Natural variant

276

1

M → V in PKU; haplotype 4. Ref.30

VAR_000975

Natural variant

277

1

Y → C in PKU.

VAR_000976

Natural variant

277

1

Y → D in PKU; haplotype 2.

VAR_000977

Natural variant

278

1

T → A in PKU.

VAR_000978

Natural variant

278

1

T → N in PKU.

VAR_000979

Natural variant

280

1

E → K in PKU; haplotypes 1,2,4,16,38; partial residual activity. Ref.15 Ref.34

VAR_000980

Natural variant

281

1

P → L in PKU; haplotypes 1,4. Ref.20 Ref.21 Ref.34

VAR_000981

Natural variant

282

1

D → N in PKU; haplotype 1.

VAR_000982

Natural variant

283

1

I → F in PKU; haplotype 21.

VAR_000983

Natural variant

283

1

I → N in PKU; severe.

VAR_000984

Natural variant

297

1

R → C in PKU; haplotype 4.

VAR_000985

Natural variant

297

1

R → H in PKU.

VAR_000986

Natural variant

299

1

F → C in PKU; haplotype 8. Ref.34

VAR_000987

Natural variant

300

1

A → S in PKU; haplotype 1.

VAR_000988

Natural variant

300

1

A → V in PKU.

VAR_000989

Natural variant

303

1

S → P in PKU; haplotype 5.

VAR_000990

Natural variant

304

1

Q → R in PKU.

VAR_000991

Natural variant

306

1

I → V in non-PKU HPA; haplotype 4. Ref.24

VAR_000992

Natural variant

309

1

A → D in PKU; haplotype 7.

VAR_000993

Natural variant

309

1

A → V in PKU.

VAR_000994

Natural variant

310

1

S → F in PKU; haplotype 7.

VAR_000995

Natural variant

311

1

L → P in PKU; haplotypes 1,7,10. Ref.14 Ref.16

VAR_000996

Natural variant

314

1

P → H in PKU.

VAR_000997

Natural variant

318

1

I → T in PKU; partial loss of activity. Ref.50

VAR_011574

Natural variant

322

1

A → G in PKU; haplotype 12.

VAR_000998

Natural variant

322

1

A → T in PKU; haplotype 1.

VAR_000999

Natural variant

325

1

Y → C in PKU.

VAR_009245

Natural variant

330

1

E → D in PKU.

VAR_009246

Natural variant

331

1

F → L in PKU; haplotype 1. Ref.32

VAR_001000

Natural variant

333

1

L → F in PKU.

VAR_001001

Natural variant

334

1

C → S in PKU.

VAR_001002

Natural variant

337

1

G → V in PKU.

VAR_001003

Natural variant

338

1

D → Y in PKU; haplotype 4.

VAR_001004

Natural variant

341

1

K → R in PKU.

VAR_001005

Natural variant

341

1

K → T in PKU.

VAR_001006

Natural variant

342

1

A → T in PKU; haplotype 5.

VAR_001007

Natural variant

343

1

Y → C in PKU.

VAR_001008

Natural variant

344

1

G → R in PKU.

VAR_009247

Natural variant

344

1

G → V in PKU.

VAR_009248

Natural variant

345

1

A → S in PKU.

VAR_001009

Natural variant

345

1

A → T in PKU; haplotype 7.

VAR_001010

Natural variant

347

1

L → F in PKU.

VAR_001011

Natural variant

348

1

L → V in PKU; mild haplotype 9.

VAR_001012

Natural variant

349

1

S → L in PKU; severe. Ref.39

VAR_001013

Natural variant

349

1

S → P in PKU; haplotypes 1,4. Ref.39

VAR_001014

Natural variant

350

1

S → T in PKU; haplotype 2.

VAR_001015

Natural variant

357

1

C → G in PKU.

VAR_011575

Natural variant

362

1

P → T in PKU. Ref.40

VAR_001016

Natural variant

364 – 368

5

Missing in PKU. Ref.17 Ref.26

VAR_001018

Natural variant

364

1

Missing in PKU; haplotype 5. Ref.17

VAR_001017

Natural variant

366

1

P → H in PKU.

VAR_001019

Natural variant

372

1

T → S in PKU.

VAR_001020

Natural variant

377

1

Y → C in PKU; haplotype 4.

VAR_001021

Natural variant

380

1

T → M in non-PKU HPA; haplotype 4.

VAR_001022

Natural variant

386

1

Y → C in PKU; common mutation.

VAR_001023

Natural variant

387

1

Y → H in PKU; haplotype 1.

VAR_001024

Natural variant

388

1

V → L in PKU. Ref.41

VAR_001025

Natural variant

388

1

V → M in PKU; haplotypes 1,4. Ref.41

VAR_001026

Natural variant

390

1

E → G in non-PKU HPA; haplotype 4. Ref.34 Ref.29

VAR_001027

Natural variant

394

1

D → A in PKU. Ref.34

VAR_001028

Natural variant

394

1

D → H in PKU. Ref.34

VAR_001029

Natural variant

395

1

A → G in PKU.

VAR_001030

Natural variant

395

1

A → P in PKU; haplotype 1.

VAR_001031

Natural variant

399 – 400

2

Missing in PKU; haplotype 7.

VAR_001032

Natural variant

403

1

A → V in non-PKU HPA and PKU; haplotype 43. Ref.34

VAR_001033

Natural variant

407

1

P → S in PKU.

VAR_011576

Natural variant

408

1

R → Q in PKU; haplotypes 4,12. Ref.25 Ref.34 Ref.39 Ref.42

VAR_001034

Natural variant

408

1

R → W in PKU; haplotypes 1,2,4,5,13,34, 41,44; most common mutation. Ref.25 Ref.34 Ref.39 Ref.42

VAR_001035

Natural variant

410

1

F → S in PKU; mild.

VAR_009249

Natural variant

413

1

R → P in non-PKU HPA and PKU; haplotype 4. Ref.45

VAR_001036

Natural variant

413

1

R → S in PKU; haplotype 1.

VAR_001037

Natural variant

414

1

Y → C in PKU; haplotype 4. Ref.34

VAR_001038

Natural variant

415

1

D → N in non-PKU HPA; haplotype 1. Ref.24

VAR_001039

Natural variant

418

1

T → P in PKU; haplotype 4.

VAR_001040

Natural variant

430

1

L → P in PKU.

VAR_001041

Natural variant

447

1

A → D in PKU.

VAR_001042

Experimental info

Sequence conflict

183

1

E → G in AAH26251. Ref.3

Secondary structure

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452

Helix Strand Turn

Details...

Helix

125 – 133

9

Helix

140 – 142

3

Turn

147 – 150

4

Helix

152 – 167

16

Helix

181 – 195

15

Helix

198 – 201

4

Helix

204 – 217

14

Helix

227 – 238

12

Beta strand

241 – 244

4

Helix

251 – 258

8

Turn

259 – 261

3

Beta strand

262 – 265

4

Helix

283 – 289

7

Helix

291 – 294

4

Helix

297 – 310

14

Helix

315 – 327

13

Turn

328 – 331

4

Beta strand

333 – 336

4

Beta strand

339 – 342

4

Helix

345 – 348

4

Helix

351 – 357

7

Beta strand

359 – 366

8

Helix

369 – 372

4

Beta strand

379 – 381

3

Beta strand

384 – 390

7

Helix

392 – 404

13

Beta strand

409 – 415

7

Turn

416 – 419

4

Beta strand

420 – 424

5

Helix

426 – 450

25

Sequences

	Sequence		Length	Mass (Da)
	P00439-1 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 018F00EBBBDDCE2F	FASTA	452	51,862
	10 20 30 40 50 60 MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK VLRLFEENDV 70 80 90 100 110 120 NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH DIGATVHELS RDKKKDTVPW 130 140 150 160 170 180 FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYM 190 200 210 220 230 240 EEEKKTWGTV FKTLKSLYKT HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF 250 260 270 280 290 300 RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA 310 320 330 340 350 360 QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS FGELQYCLSE 370 380 390 400 410 420 KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR NFAATIPRPF SVRYDPYTQR 430 440 450 IEVLDNTQQL KILADSINSE IGILCSALQK IK

References

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[1]	"Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase." Kwok S.C.M., Ledley F.D., Dilella A.G., Robson K.J.H., Woo S.L.C. Biochemistry 24:556-561(1985) [PubMed: 2986678] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	Scriver C.R., Nowacki P.M., Byck S., Prevost L. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[4]	"A monoclonal antibody to aromatic amino acid hydroxylases. Identification of the epitope." Cotton R.G., McAdam W., Jennings I., Morgan F.J. Biochem. J. 255:193-196(1988) [PubMed: 2461704] [Abstract] Cited for: PROTEIN SEQUENCE OF 131-144.
[5]	"Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria." Erlandsen H., Fusetti F., Martinez A., Hough E., Flatmark T., Stevens R.C. Nat. Struct. Biol. 4:995-1000(1997) [PubMed: 9406548] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 117-424.
[6]	"Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0-A resolution." Erlandsen H., Flatmark T., Stevens R.C., Hough E. Biochemistry 37:15638-15646(1998) [PubMed: 9843368] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 117-424.
[7]	"Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria." Fusetti F., Erlandsen H., Flatmark T., Stevens R.C. J. Biol. Chem. 273:16962-16967(1998) [PubMed: 9642259] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 117-452.
[8]	"Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase." Erlandsen H., Bjorgo E., Flatmark T., Stevens R.C. Biochemistry 39:2208-2217(2000) [PubMed: 10694386] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 118-424.
[9]	"High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin." Andersen O.A., Flatmark T., Hough E. J. Mol. Biol. 314:279-291(2001) [PubMed: 11718561] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 103-427.
[10]	"The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations." Konecki D.S., Lichter-Konecki U. Hum. Genet. 87:377-388(1991) [PubMed: 1679029] [Abstract] Cited for: REVIEW ON PKU VARIANTS.
[11]	"Heterogeneity of phenylketonuria at the clinical, protein and DNA levels." Cotton R.G. J. Inherit. Metab. Dis. 13:739-750(1990) [PubMed: 2246858] [Abstract] Cited for: REVIEW ON PKU VARIANTS.
[12]	"Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene." Eisensmith R.C., Woo S.L.C. Hum. Mutat. 1:13-22(1992) [PubMed: 1301187] [Abstract] Cited for: REVIEW ON PKU VARIANTS.
[13]	"PAH Mutation Analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus." Hoang L., Byck S., Prevost L., Scriver C.R. Nucleic Acids Res. 24:127-131(1996) [PubMed: 8594560] [Abstract] Cited for: DATABASE OF PKU VARIANTS.
[14]	"Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene." Lichter-Konecki U., Konecki D.S., Dilella A.G., Brayton K., Marvit J., Hahn T.M., Trefz F.K., Woo S.L.C. Biochemistry 27:2881-2885(1988) [PubMed: 2840952] [Abstract] Cited for: VARIANT PKU PRO-311.
[15]	"Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency." Lyonnet S., Caillaud C., Rey F., Berthelon M., Frezal J., Rey J., Munnich A. Am. J. Hum. Genet. 44:511-517(1989) [PubMed: 2564729] [Abstract] Cited for: VARIANT PKU LYS-280.
[16]	"Phenylketonuria in the Greek population. Haplotype analysis of the phenylalanine hydroxylase gene and identification of a PKU mutation." Hofman K.J., Antonarakis S.E., Missiou-Tsangaraki S., Boehm C.D., Valle D. Mol. Biol. Med. 6:245-250(1989) [PubMed: 2615649] [Abstract] Cited for: VARIANT PKU PRO-311.
[17]	"Two mutations within the coding sequence of the phenylalanine hydroxylase gene." Svensson E., Andersson B., Hagenfeldt L. Hum. Genet. 85:300-304(1990) [PubMed: 1975559] [Abstract] Cited for: VARIANT PKU LEU-364 DEL.
[18]	"Screening for mutations in the phenylalanine hydroxylase gene from Italian patients with phenylketonuria by using the chemical cleavage method: a new splice mutation." Dianzani I., Forrest S.M., Camaschella C., Saglio G., Ponzone A., Cotton R.G. Am. J. Hum. Genet. 48:631-635(1991) [PubMed: 1671810] [Abstract] Cited for: VARIANT PKU GLN-261.
[19]	"Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene." Hofman K.J., Steel G., Kazazian H.H. Jr., Valle D. Am. J. Hum. Genet. 48:791-798(1991) [PubMed: 2014802] [Abstract] Cited for: VARIANT PKU SER-255.
[20]	"Phenylketonuria missense mutations in the Mediterranean." Okano Y., Wang T., Eisensmith R.C., Longhi R., Riva E., Giovannini M., Cerone R., Romano C., Woo S.L.C. Genomics 9:96-103(1991) [PubMed: 1672294] [Abstract] Cited for: VARIANTS PKU TRP-252 AND LEU-281.
[21]	"Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing severe phenylketonuria." Dworniczak B., Grudda K., Stumper J., Bartholome K., Aulehla-Scholz C., Horst J. Genomics 9:193-199(1991) [PubMed: 1672290] [Abstract] Cited for: VARIANT PKU LEU-281.
[22]	"The identification of two mis-sense mutations at the PAH gene locus in a Turkish patient with phenylketonuria." Konecki D.S., Schlotter M., Trefz F.K., Lichter-Konecki U. Hum. Genet. 87:389-393(1991) [PubMed: 1679030] [Abstract] Cited for: VARIANTS PKU SER-48 AND GLY-221.
[23]	"A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria." Caillaud C., Lyonnet S., Rey F., Melle D., Frebourg T., Berthelon M., Vilarinho L., Vaz Osorio R., Rey J., Munnich A. J. Biol. Chem. 266:9351-9354(1991) [PubMed: 1709636] [Abstract] Cited for: VARIANT PKU ILE-94 DEL.
[24]	"Molecular basis for nonphenylketonuria hyperphenylalaninemia." Economou-Petersen E., Henriksen K.F., Guldberg P., Guettler F. Genomics 14:1-5(1992) [PubMed: 1358789] [Abstract] Cited for: VARIANTS NON-PKU HPA VAL-306 AND ASN-415.
[25]	"Identification of a missense phenylketonuria mutation at codon 408 in Chinese." Lin C.H., Hsiao K.J., Tsai T.F., Chao H.K., Su T.S. Hum. Genet. 89:593-596(1992) [PubMed: 1355066] [Abstract] Cited for: VARIANTS PKU GLN-408 AND TRP-408.
[26]	"A new 15 bp deletion in exon 11 of the phenylalanine hydroxylase gene in phenylketonuria." Jaruzelska J., Melle D., Matuszak R., Borski K., Munnich A. Hum. Mol. Genet. 1:763-764(1992) [PubMed: 1363837] [Abstract] Cited for: VARIANT PKU 364-LEU--GLU-368 DEL.
[27]	"A new PKU mutation associated with haplotype 12." Desviat L.R., Perez B., Ugarte M. Hum. Mol. Genet. 1:765-766(1992) [PubMed: 1363838] [Abstract] Cited for: VARIANT PKU LEU-244.
[28]	"Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis." Guldberg P., Henriksen K.F., Guettler F. Genomics 17:141-146(1993) [PubMed: 8406445] [Abstract] Cited for: VARIANTS PKU.
[29]	"Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria." Abadie V., Jaruzelska J., Lyonnet S., Millasseau P., Berthelon M., Rey F., Munnich A., Rey J. Hum. Mol. Genet. 2:31-34(1993) [PubMed: 8098245] [Abstract] Cited for: VARIANT NON-PKU HPA GLY-390.
[30]	"Identification of a new missense mutation in Japanese phenylketonuric patients." Goebel-Schreiner B., Schreiner R. J. Inherit. Metab. Dis. 16:950-956(1993) [PubMed: 8068076] [Abstract] Cited for: VARIANT PKU VAL-276.
[31]	"Molecular heterogeneity of nonphenylketonuria hyperphenylalaninemia in 25 Danish patients." Guldberg P., Henriksen K.F., Thoeny B., Blau N., Guettler F. Genomics 21:453-455(1994) [PubMed: 8088845] [Abstract] Cited for: VARIANTS NON-PKU HPA VAL-47; ARG-87; LEU-176 AND ALA-245.
[32]	"Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria." Benit P., Rey F., Melle D., Munnich A., Rey J. Hum. Mutat. 4:229-231(1994) [PubMed: 7833954] [Abstract] Cited for: VARIANTS PKU THR-164; ALA-171; SER-239; GLN-252 AND LEU-331.
[33]	"PKU mutation (D143G) associated with an apparent high residual enzyme activity: expression of a kinetic variant form of phenylalanine hydroxylase in three different systems." Knappskog P.M., Eiken H.G., Martinez A., Bruland O., Apold J., Flatmark T. Hum. Mutat. 8:236-246(1996) [PubMed: 8889583] [Abstract] Cited for: CHARACTERIZATION OF VARIANT PKU GLY-143.
[34]	"Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations." Guldberg P., Mallmann R., Henriksen K.F., Guettler F. Hum. Mutat. 8:276-279(1996) [PubMed: 8889590] [Abstract] Cited for: VARIANTS PKU LEU-40; SER-46; SER-48; 63-PRO-ASN-64; THR-65; SER-68; CYS-241; ALA-245; GLN-261; LYS-280; LEU-281; CYS-299; GLY-390; HIS-394; VAL-403; TRP-408 AND CYS-414.
[35]	"Two novel PAH gene mutations detected in Italian phenylketonuric patients." Argiolas A., Bosco P., Cali F., Ceratto N., Anello G., Riva E., Biasucci G., Carducci C., Romano V. Hum. Genet. 99:275-278(1997) [PubMed: 9048935] [Abstract] Cited for: VARIANTS PKU CYS-204 AND SER-207.
[36]	"Prediction of multiple hypermutable codons in the human PAH gene: codon 280 contains recurrent mutations in Quebec and other populations." Byck S., Tyfield L., Carter K., Scriver C.R. Hum. Mutat. 9:316-321(1997) [PubMed: 9101291] [Abstract] Cited for: VARIANTS PKU.
[37]	"In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function." Waters P.J., Parniak M.A., Nowacki P., Scriver C.R. Hum. Mutat. 11:4-17(1998) [PubMed: 9450897] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS.
[38]	"Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia." Bosco P., Cali F., Meli C., Mollica F., Zammarchi E., Cerone R., Vanni C., Palillo L., Greco D., Romano V. Hum. Mutat. 11:240-243(1998) [PubMed: 9521426] [Abstract] Cited for: VARIANTS PKU AND NON-PKU.
[39]	"Molecular basis of phenylketonuria in Venezuela: presence of two novel null mutations." de Lucca M., Perez B., Desviat L.R., Ugarte M. Hum. Mutat. 11:354-359(1998) [PubMed: 9600453] [Abstract] Cited for: VARIANTS PKU GLN-243; LEU-349 AND TRP-408.
[40]	"Two novel mutations in exon 11 of the PAH gene (1163/1164 del TG and P362T) associated with classic phenylketonuria and mild phenylketonuria." Mallolas J., Campistol J., Lambruscini N., Vilaseca M.A., Cambra J.F., Estivill X., Milo M. Hum. Mutat. 11:482-482(1998) [PubMed: 10200057] [Abstract] Cited for: VARIANT PKU THR-362.
[41]	"Identification of three novel mutations in Korean phenylketonuria patients: R53H, N207D, and Y325X." Park Y.S., Seoung C.S., Lee S.W., Oh K.H., Lee D.H., Yim J. Hum. Mutat. Suppl. 1:S121-S122(1998) [PubMed: 9452061] [Abstract] Cited for: VARIANTS PKU HIS-53; ASP-207 AND LEU-388.
[42]	"Identification of seven new mutations in the phenylalanine hydroxylase gene, associated with hyperphenylalaninemia in the Belgian population." Michiels L., Francois B., Raus J., Vandevyver C. Hum. Mutat. Suppl. 1:S123-S124(1998) [PubMed: 9452062] [Abstract] Cited for: VARIANTS PKU PHE-39 DEL; THR-65; GLN-158; ILE-167; ALA-190; CYS-241 AND TRP-408.
[43]	"Mutation spectrum and phenylalanine hydroxylase RFLP/VNTR background in 44 Romanian phenylketonuric alleles." Popescu T., Blazkova M., Kozak L., Jebeleanu G., Popescu A. Hum. Mutat. 12:314-319(1998) [PubMed: 9792407] [Abstract] Cited for: VARIANTS PKU.
[44]	"Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene." Waters P.J., Parniak M.A., Hewson A.S., Scriver C.R. Hum. Mutat. 12:344-354(1998) [PubMed: 9792411] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS PKU ASP-104 AND ASN-157.
[45]	"Mutation analysis of the phenylalanine hydroxylase gene and its clinical implications in two Japanese patients with non-phenylketonuria hyperphenylalaninemia." Kibayashi M., Nagao M., Chiba S. J. Hum. Genet. 43:231-236(1998) [PubMed: 9852673] [Abstract] Cited for: VARIANTS NON-PKU HPA CYS-241; GLN-243 AND PRO-413.
[46]	"Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations." Hennermann J.B., Vetter B., Wolf C., Windt E., Buehrdel P., Seidel J., Moench E., Kulozik A.E. Hum. Mutat. 15:254-260(2000) [PubMed: 10679941] [Abstract] Cited for: VARIANTS PKU.
[47]	"Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine." Gjetting T., Petersen M., Guldberg P., Guettler F. Am. J. Hum. Genet. 68:1353-1360(2001) [PubMed: 11326337] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS PKU.
[48]	"Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria." Acosta A.X., Silva W.A. Jr., Carvalho T.M., Gomes M., Zago M.A. Hum. Mutat. 17:122-130(2001) [PubMed: 11180595] [Abstract] Cited for: VARIANTS PKU.
[49]	"Molecular analysis of phenylketonuria (PKU) in newborns from Texas." Yang Y., Drummond-Borg M., Garcia-Heras J. Hum. Mutat. 17:523-523(2001) [PubMed: 11385716] [Abstract] Cited for: VARIANTS PKU, VARIANTS HPA.
[50]	"A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics." Gjetting T., Romstad A., Haavik J., Knappskog P.M., Acosta A.X., Silva W.A. Jr., Zago M.A., Guldberg P., Guettler F. Mol. Genet. Metab. 73:280-284(2001) [PubMed: 11461196] [Abstract] Cited for: VARIANTS PKU TRP-252 AND THR-318, VARIANT GLU-274.
+	Additional computationally mapped references.

Web resources

PAHdb

Phenylalanine hydroxylase locus knowledgebase

GeneReviews

Wikipedia

Phenylalanine hydroxylase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

K03020 mRNA. Translation: AAA60082.1.
U49897 mRNA. Translation: AAC51772.1.
S61296 mRNA. Translation: AAD13926.1.
BC026251 mRNA. Translation: AAH26251.1.

IPI

IPI00017579.

PIR

WHHUF. A00508.

RefSeq

NP_000268.1.

UniGene

Hs.643451

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DMW	X-ray	2.00	A	118-424	[»]
1J8T	X-ray	1.70	A	103-427	[»]
1J8U	X-ray	1.50	A	103-427	[»]
1KW0	X-ray	2.50	A	103-427	[»]
1LRM	X-ray	2.10	A	103-427	[»]
1MMK	X-ray	2.00	A	103-427	[»]
1MMT	X-ray	2.00	A	103-427	[»]
1PAH	X-ray	2.00	A	117-424	[»]
1TDW	X-ray	2.10	A	117-424	[»]
1TG2	X-ray	2.20	A	117-424	[»]
2PAH	X-ray	3.10	A/B	118-452	[»]
3PAH	X-ray	2.00	A	117-424	[»]
4PAH	X-ray	2.00	A	117-424	[»]
5PAH	X-ray	2.10	A	117-424	[»]
6PAH	X-ray	2.15	A	117-424	[»]

SMR

P00439. Positions 19-427.

ModBase

Search...

PTM databases

PhosphoSite

P00439.

2-D gel databases

HSC-2DPAGE

P00439.

Proteomic databases

PRIDE

P00439.

Genome annotation databases

Ensembl

ENSG00000171759. Homo sapiens. [Contig view]

GeneID

5053.

KEGG

hsa:5053.

NMPDR

fig|9606.3.peg.8135.

UCSC

uc001tjq.1. human.

Organism-specific databases

GeneCards

GC12M101737.

H-InvDB

HIX0010929.

HGNC

HGNC:8582. PAH.

MIM

261600. phenotype.
612349. gene.

Orphanet

716. Phenylketonuria.

PharmGKB

PA32911.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P00439.

HOVERGEN

P00439.

OMA

P00439. QETSYIE.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-12066.

BRENDA

1.14.16.1. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

ArrayExpress

P00439.

Bgee

P00439.

CleanEx

HS_PAH.

GermOnline

ENSG00000171759. Homo sapiens.

Family and domain databases

InterPro

IPR002912. ACT_bd.
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]

Gene3D

G3DSA:1.10.800.10. Aaa_hydroxylase. 1 hit.

PANTHER

PTHR11473. Aaa_hydroxylase. 1 hit.

Pfam

PF01842. ACT. 1 hit.
PF00351. Biopterin_H. 1 hit.
[Graphical view]

PIRSF

PIRSF000336. TH. 1 hit.

PRINTS

PR00372. FYWHYDRXLASE.

ProDom

PD002559. Aaa_hydroxylase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

TIGRFAMs

TIGR01268. Phe4hydrox_tetr. 1 hit.

PROSITE

PS00367. BIOPTERIN_HYDROXYL. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00668. Epinephrine.
DB00120. L-Phenylalanine.
DB01235. Levodopa.
DB00368. Norepinephrine.
DB00360. Tetrahydrobiopterin.

NextBio

19476.

SOURCE

Search...

Entry information

Entry name

PH4H_HUMAN

Accession

Primary (citable) accession number: P00439
Secondary accession number(s): Q16717, Q8TC14

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	July 7, 2009
This is version 133 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)