Human Gene PAH (uc001tjq.1)
  Description: Homo sapiens phenylalanine hydroxylase (PAH), mRNA.
RefSeq Summary (NM_000277): This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017].
Transcript (Including UTRs)
   Position: hg19 chr12:103,232,104-103,311,381 Size: 79,278 Total Exon Count: 13 Strand: -
Coding Region
   Position: hg19 chr12:103,232,953-103,310,908 Size: 77,956 Coding Exon Count: 13 

Page IndexSequence and LinksUniProtKB CommentsPrimersGenetic AssociationsMalaCards
CTDGene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein Structure
Other SpeciesGO AnnotationsmRNA DescriptionsPathwaysOther NamesGeneReviews
Model InformationMethods
Data last updated at UCSC: 2013-06-14

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr12:103,232,104-103,311,381)mRNA (may differ from genome)Protein (452 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
AlphaFoldBioGPSEnsemblEntrez GeneExonPrimerGeneCards
WikipediaBioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Phenylalanine-4-hydroxylase; Short=PAH; EC=; AltName: Full=Phe-4-monooxygenase;
CATALYTIC ACTIVITY: L-phenylalanine + tetrahydrobiopterin + O(2) = L-tyrosine + 4a-hydroxytetrahydrobiopterin.
COFACTOR: Fe(2+) 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.
BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=150 uM for L-Phe with BH(4) as cofactor; KM=30 uM for BH(4); Vmax=3640 nmol/min/mg enzyme with BH(4) as cofactor (preincubated with L-Phe); Vmax=1230 nmol/min/mg enzyme with BH(4) as cofactor (preincubated with BH(4)); Temperature dependence: Optimum temperature is 50 degrees Celsius;
PATHWAY: Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 1/6.
SUBUNIT: Homodimer and homotetramer.
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.
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.
DISEASE: 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.
DISEASE: Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600]. HPA is the mildest form of phenylalanine hydroxylase deficiency.
SIMILARITY: Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.
SIMILARITY: Contains 1 ACT domain.
WEB RESOURCE: Name=PAHdb; Note=Phenylalanine hydroxylase locus knowledgebase; URL="";
WEB RESOURCE: Name=GeneReviews; URL="";
WEB RESOURCE: Name=Wikipedia; Note=Phenylalanine hydroxylase entry; URL="";

-  Primer design for this transcript

Primer3Plus can design qPCR Primers that straddle exon-exon-junctions, which amplify only cDNA, not genomic DNA.
Click here to load the transcript sequence and exon structure into Primer3Plus

Exonprimer can design one pair of Sanger sequencing primers around every exon, located in non-genic sequence.
Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): PAH
CDC HuGE Published Literature: PAH
Positive Disease Associations: phenylketonuria
Related Studies:
  1. phenylketonuria
    Hertzberg M et al. 1989, Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria., American journal of human genetics. 1989 Mar;44(3):382-7. [PubMed 2563633]

-  MalaCards Disease Associations
  MalaCards Gene Search: PAH
Diseases sorted by gene-association score: phenylketonuria* (1737), mild phenylketonuria* (768), mild hyperphenylalaninemia* (378), classic phenylketonuria* (371), tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria* (350), hyperphenylalaninemia (26), norse (18), amino acid metabolic disorder (14), tyrosinemia (9), c3 deficiency (8), tetrahydrobiopterin deficiency (6), keratomalacia (5), maple syrup urine disease, type ii (4), inherited metabolic disorder (2)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 173.23 RPKM in Liver
Total median expression: 203.43 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -186.24473-0.394 Picture PostScript Text
3' UTR -169.03849-0.199 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR002912 - 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

Pfam Domains:
PF00351 - Biopterin-dependent aromatic amino acid hydroxylase
PF01842 - ACT domain

SCOP Domains:
56534 - Aromatic aminoacid monoxygenases, catalytic and oligomerization domains
55021 - ACT-like

Protein Data Bank (PDB) 3-D Structure
MuPIT help
1DMW - X-ray MuPIT 1J8T - X-ray MuPIT 1J8U - X-ray MuPIT 1KW0 - X-ray MuPIT 1LRM - X-ray MuPIT 1MMK - X-ray MuPIT 1MMT - X-ray MuPIT 1PAH - X-ray MuPIT 1TDW - X-ray MuPIT 1TG2 - X-ray MuPIT 2PAH - X-ray MuPIT 3PAH - X-ray MuPIT 4ANP - X-ray MuPIT 4PAH - X-ray MuPIT 5PAH - X-ray MuPIT 6PAH - X-ray MuPIT

ModBase Predicted Comparative 3D Structure on P00439
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserGenome BrowserGenome BrowserGenome BrowserNo ortholog
Gene DetailsGene Details Gene DetailsGene Details 
Gene SorterGene Sorter Gene SorterGene Sorter 
 Protein SequenceProtein SequenceProtein SequenceProtein Sequence 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0003824 catalytic activity
GO:0004497 monooxygenase activity
GO:0004505 phenylalanine 4-monooxygenase activity
GO:0005506 iron ion binding
GO:0016491 oxidoreductase activity
GO:0016714 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen
GO:0046872 metal ion binding

Biological Process:
GO:0006559 L-phenylalanine catabolic process
GO:0008152 metabolic process
GO:0008652 cellular amino acid biosynthetic process
GO:0009072 aromatic amino acid family metabolic process
GO:0042136 neurotransmitter biosynthetic process
GO:0042423 catecholamine biosynthetic process
GO:0055114 oxidation-reduction process

Cellular Component:
GO:0005829 cytosol

-  Descriptions from all associated GenBank mRNAs
  AX512666 - Sequence 1 from Patent WO02063043.
U49897 - Homo sapiens phenylalanine hydroxylase (PAH) mRNA, complete cds.
K03020 - Human phenylalanine hydroxylase mRNA, complete cds.
L47726 - Homo sapiens phenylalanine hydroxylase (PAH) mutant Q20stop mRNA.
BC026251 - Homo sapiens phenylalanine hydroxylase, mRNA (cDNA clone MGC:22457 IMAGE:4767736), complete cds.
AK313383 - Homo sapiens cDNA, FLJ93916, highly similar to Homo sapiens phenylalanine hydroxylase (PAH), mRNA.
HQ447614 - Synthetic construct Homo sapiens clone IMAGE:100070960; CCSB013103_01 phenylalanine hydroxylase (PAH) gene, encodes complete protein.
KJ897291 - Synthetic construct Homo sapiens clone ccsbBroadEn_06685 PAH gene, encodes complete protein.
KR711255 - Synthetic construct Homo sapiens clone CCSBHm_00021550 PAH (PAH) mRNA, encodes complete protein.
KR711256 - Synthetic construct Homo sapiens clone CCSBHm_00021594 PAH (PAH) mRNA, encodes complete protein.
KR711257 - Synthetic construct Homo sapiens clone CCSBHm_00021717 PAH (PAH) mRNA, encodes complete protein.
KR711258 - Synthetic construct Homo sapiens clone CCSBHm_00021904 PAH (PAH) mRNA, encodes complete protein.
AK298419 - Homo sapiens cDNA FLJ56667 complete cds, highly similar to Phenylalanine-4-hydroxylase (EC
CU693178 - Synthetic construct Homo sapiens gateway clone IMAGE:100022295 5' read PAH mRNA.
MP429740 - Sequence 1 from Patent EP3574923.
JD285083 - Sequence 266107 from Patent EP1572962.
JD084015 - Sequence 65039 from Patent EP1572962.
JD410388 - Sequence 391412 from Patent EP1572962.
JD173077 - Sequence 154101 from Patent EP1572962.
JD313031 - Sequence 294055 from Patent EP1572962.
S61296 - PAH=phenylalanine hydroxylase {exon 11/12, mutant E390G} [human, lymphocytes, mRNA Partial Mutant, 75 nt].
S61396 - PAH=phenylalanine hydroxylase {exon 9/10, mutant L333F} [human, lymphocytes, mRNA Partial Mutant, 79 nt].
JD103669 - Sequence 84693 from Patent EP1572962.
JD101063 - Sequence 82087 from Patent EP1572962.
JD126566 - Sequence 107590 from Patent EP1572962.
JD437747 - Sequence 418771 from Patent EP1572962.
JD143279 - Sequence 124303 from Patent EP1572962.
JD123159 - Sequence 104183 from Patent EP1572962.
JD416798 - Sequence 397822 from Patent EP1572962.
JD201829 - Sequence 182853 from Patent EP1572962.
JD435535 - Sequence 416559 from Patent EP1572962.
JD114555 - Sequence 95579 from Patent EP1572962.
JD467824 - Sequence 448848 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa00360 - Phenylalanine metabolism
hsa00400 - Phenylalanine, tyrosine and tryptophan biosynthesis
hsa01100 - Metabolic pathways

BioCyc Knowledge Library
PHENYLALANINE-DEG1-PWY - phenylalanine degradation I (aerobic)
TYRSYN2 - tyrosine biosynthesis II

Reactome (by CSHL, EBI, and GO)

Protein P00439 (Reactome details) participates in the following event(s):

R-HSA-71118 PAH tetramer hydroxylates L-Phe to L-Tyr
R-HSA-71182 Phenylalanine and tyrosine catabolism
R-HSA-6788656 Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism
R-HSA-71291 Metabolism of nitrogenous molecules
R-HSA-1430728 Metabolism

-  Other Names for This Gene
  Alternate Gene Symbols: NM_000277, NP_000268, P00439, PH4H_HUMAN, Q16717, Q8TC14
UCSC ID: uc001tjq.1
RefSeq Accession: NM_000277
Protein: P00439 (aka PH4H_HUMAN)
CCDS: CCDS9092.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene PAH:
dystonia-ov (Hereditary Dystonia Overview)
pku (Phenylalanine Hydroxylase Deficiency)

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_000277.1
exon count: 13CDS single in 3' UTR: no RNA size: 2680
ORF size: 1359CDS single in intron: no Alignment % ID: 99.89
txCdsPredict score: 2816.00frame shift in genome: no % Coverage: 100.00
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.