Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	452	12q23.2	PAH	phenylalanine hydroxylase
Mouse	-	453	10 43.64 cM	Pah	phenylalanine hydroxylase
Rat	-	453	7q13	Pah	phenylalanine hydroxylase

Previous and Unofficial Names

Phenylalanine 4-monooxygenase | PH | phe-4-monooxygenase | phenylalanine-4-hydroxylase

Database Links
Alphafold	P00439 (Hs), P16331 (Mm), P04176 (Rn)
BRENDA	1.14.16.1
CATH/Gene3D	1.10.800.10
ChEMBL Target	CHEMBL3076 (Hs), CHEMBL3077 (Rn)
DrugBank Target	P00439 (Hs)
Ensembl Gene	ENSG00000171759 (Hs), ENSMUSG00000020051 (Mm), ENSRNOG00000004302 (Rn)
Entrez Gene	5053 (Hs), 18478 (Mm), 24616 (Rn)
Human Protein Atlas	ENSG00000171759 (Hs)
KEGG Enzyme	1.14.16.1
KEGG Gene	hsa:5053 (Hs), mmu:18478 (Mm), rno:24616 (Rn)
OMIM	612349 (Hs)
Orphanet	ORPHA124068 (Hs)
Pharos	P00439 (Hs)
SynPHARM	79537 (in complex with sapropterin)
UniProtKB	P00439 (Hs), P16331 (Mm), P04176 (Rn)
Wikipedia	PAH (Hs)

Enzyme Reaction
EC Number: 1.14.16.1 L-phenylalanine + O2 -> L-tyrosine

Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference L-phenylalanine N/A - -

Products
Product Species Reference L-tyrosine Human

Cofactors
Cofactor Species Comments Reference sapropterin Human

Endogenous activators (Rat)

Protein kinase A-mediated phosphorylation  [1]

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Action Value Parameter Reference sapropterin Hs Activation 5.4 pKi 3 ⤷ pKi 5.4 (Ki 4x10-6 M) [3] Description: Binding affinity for human PAH.
Activator Comments
L-Phenylalanine hydroxylase is the probable primary target of the approved activating drug sapropterin.

Inhibitors
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Action Value Parameter Reference α-methylphenylalanine Rn Inhibition - - 2 ⤷ [2] fenclonine Hs Inhibition - - ⤷
View species-specific inhibitor tables

Clinically-Relevant Mutations and Pathophysiology
Disease:  Classical phenylketonuria Synonyms: Phenylketonuria [OMIM: 261600] [Disease Ontology: DOID:9281] Disease Ontology: DOID:9281 OMIM: 261600 Orphanet: ORPHA79254 Role:  Genetic deficiency of phenylalanine hydroxylase leads to elevated plasma Phe levels (hyperphenylalaninaemia), reduced brain levels of monoamine neurotransmitters, and ultimately causes neurocognitive dysfunction. Drugs:  Sapropterin Comments:  In May 2018, the US FDA approved a novel enzyme therapy for adult PKU patients for whom current methods of controlling Phe levels are inadequate. Palynziq® (pegvaliase-pqpz) is a recombinant and pegylated form of phenylalanine ammonia lyase, an enzyme derived from the filamentous cyanobacterium Anabaena variabilis. Administration of pegvaliase in humans reduces plasma Phe levels by converting it to trans-cinnamic acid and trace amounts of ammonia. In the EU, pegvaliase can be used under orphan drug designation (May 2018). References:  4
Disease:  Maternal hyperphenylalaninemia OMIM: 261600 Orphanet: ORPHA2209
Disease:  Mild hyperphenylalaninemia OMIM: 261600 Orphanet: ORPHA79651 Drugs:  Sapropterin
Disease:  Mild phenylketonuria Synonyms: Phenylketonuria [OMIM: 261600] [Disease Ontology: DOID:9281] Disease Ontology: DOID:9281 OMIM: 261600 Orphanet: ORPHA79253 Drugs:  Sapropterin
Disease:  Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria Orphanet: ORPHA293284 Drugs:  Sapropterin