PAH

Protein identityUniProt · HPA

UniProt accession

P00439

Gene

PAH

Ensembl

ENSG00000171759

Chromosome

12

Canonical length

452 aa

Protein class

Disease related genes, Enzymes, FDA approved drug targets, Human disease related genes, Metabolic proteins, Predicted intracellular proteins

Subcellular location

Endoplasmic reticulum,Vesicles

Quaternary structure

Homotetramer

OverviewNCBI Gene

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]

Canonical amino-acid sequenceUniProt

452 residues, UniProt reviewed canonical sequence.

>P00439|PAH
     1  MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK VLRLFEENDV
    61  NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH DIGATVHELS RDKKKDTVPW
   121  FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYM
   181  EEEKKTWGTV FKTLKSLYKT HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF
   241  RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
   301  QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS FGELQYCLSE
   361  KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR NFAATIPRPF SVRYDPYTQR
   421  IEVLDNTQQL KILADSINSE IGILCSALQK IK

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against PAH can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.25

Highest tissue expression

1,317 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about PAH.

Disease | AllUniProt

Conditions PAH is implicated in, by any mechanism.

• Phenylalanine hydroxylase deficiency (PAH deficiency) MIM:261600

Disease | GeneticClinVar

897 pathogenic / likely-pathogenic of 1,698 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Phenylketonuria
• PAH-related disorder
• Inborn genetic diseases
• Hyperphenylalaninemia
• See cases

ReferencesPubMed · IEDB

Publications for PAH from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

1.5

gnomAD pLI

0

gnomAD missense Z

-0.65

DepMap mean gene effect

0.02

DepMap dependency class

none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• catecholamine biosynthetic process
• L-phenylalanine catabolic process
• amino acid biosynthetic process
• tyrosine biosynthetic process

Molecular functions

• iron ion binding
• phenylalanine 4-monooxygenase activity

Cellular components

• cytosol

Protein domainsUniProt · Pfam · InterPro

• Aromatic amino acid hydroxylase
• ACT domain
• Aromatic amino acid hydroxylase, iron/copper binding site
• Tyrosine 3-monooxygenase-like
• Aromatic amino acid hydroxylase, C-terminal
• Aromatic amino acid monoxygenase, C-terminal domain superfamily
• Aromatic amino acid hydroxylase superfamily
• ACT-like domain
• Biopterin-dependent aromatic amino acid hydroxylase
• Phenylalanine-4-hydroxylase, tetrameric form
• Eukaryotic phenylalanine-4-hydroxylase, catalytic domain
• ACT domain

KeywordsUniProt

• Allosteric enzyme
• Iron
• Metal-binding
• Monooxygenase
• Oxidoreductase
• Phenylalanine catabolism
• Phenylketonuria
• Phosphoprotein