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Oxidoreductases | Transferases | Hydrolases | Lyases | Isomerases | Ligases

Basic Information

Enzyme Number

Official Name

phenylalanine 4-monooxygenase

Name from literature

phenylalanine hydroxylase

Pathway from literature

hepatic phenylalanine metabolism

Pathway from KEGG

Amino Acid Metabolism; Phenylalanine, tyrosine and tryptophan biosynthesis; map00400


Human (9606)

Genome localization

12q22-q24.2[5053 ],


The active centre contains mononuclear iron(II). The reaction involves an arene oxide that rearranges to give the phenolic hydroxy group. This results in the hydrogen at C-4 migrating to C-3 and in part being retained. This process is known as the NIH-shift. The 4a-hydroxytetrahydrobiopterin formed can dehydrate to 6,7-dihydrobiopterin, both spontaneously and by the action of EC, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydrobiopterin can be enzymically reduced back to tetrahydrobiopterin, by EC, 6,7-dihydropteridine reductase, or slowly rearranges into the more stable compound 7,8-dihydrobiopterin.

Rate-limiting Description

"Cumulatively these findings suggested that TD was related to phenylalanine metabolism and thus that sequence variants in the gene for phenylalanine hydroxylase (PAH), the rate-limiting enzyme in the catabolism of phenylalanine, could be associated with TD susceptibility." (16402341)

Regulatory Information

Upstream transcription factor


Regulatory type



"Phosphorylation and mutations of Ser(16) in human phenylalanine hydroxylase." (12185072)

regulatory enzyme;

"The catalytic activity of phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase EC is regulated by three main mechanisms, i.e. substrate (l-phenylalanine, L-Phe) activation, pterin cofactor inhibition and phosphorylation of a single serine (Ser16) residue." (12603331)

key enzyme;

"Phenylalanine hydroxylase (PAH) is the key enzyme in the catabolism of L-Phe. " (15493924#10444341)

transcriptional factor;REST(5978)

"This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element-1 silencing transcription factor) to 1946 locations in the human genome." (17540862)




P00439:from_uniprot:16_Phosphoserine; by PKA

Gene ontology

Gene ontology

GO:0016597 (F) amino acid binding [P00439 ];
GO:0006559 (P) L-phenylalanine catabolic process [P00439 ];
GO:0042136 (P) neurotransmitter biosynthetic process [P00439 ];
GO:0005506 (F) iron ion binding [P00439 ];
GO:0004505 (F) phenylalanine 4-monooxygenase activity [P00439 ];
GO:0008652 (P) amino acid biosynthetic process [P00439 ];
GO:0042423 (P) catecholamine biosynthetic process [P00439 ];
GO:0055114 (P) oxidation reduction [P00439 ];

Disease relevance


Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600]. HPA is the mildest form of phenylalanine hydroxylase deficiency [P00439 ];

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 [P00439 ];

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 [P00439 ];




Entrez Gene




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  Last Modified: 2009-03-24  
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