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Phenylalanine hydroxylase
predicted 3D structure of phenylalanine hydroxylase
Available structures: 1dmw, 1j8t, 1j8u, 1kw0, 1lrm, 1mmk, 1mmt, 1pah, 1phz, 1tdw, 1tg2, 2pah, 2phm, 3pah, 4pah, 5pah, 6pah
Identifiers
Symbol(s)	PAH; PKU; PKU1
External IDs	OMIM: 261600 MGI: 97473 Homologene: 234
Gene Ontology Molecular Function: • monooxygenase activity • phenylalanine 4-monooxygenase activity • iron ion binding • amino acid binding • metal ion binding Biological Process: • L-phenylalanine catabolic process • metabolic process • amino acid biosynthetic process • aromatic amino acid family metabolic process
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	5053	18478
Ensembl	ENSG00000171759	ENSMUSG00000020051
Uniprot	P00439	Q3UEH8
Refseq	NM_000277 (mRNA) NP_000268 (protein)	NM_008777 (mRNA) NP_032803 (protein)
Location	Chr 12: 101.76 - 101.84 Mb	Chr 10: 86.95 - 87.01 Mb
Pubmed search	[1]	[2]

Phenylalanine hydroxylase (EC 1.14.16.1) is an enzyme which catalyses the reaction causing the addition of an hydroxyl group to the end of the 6-carbon aromatic ring of phenylalanine, such that it becomes tyrosine:

Phenylalanine

Tyrosine

Phenylalanine hydroxylase is the rate-limiting enzyme of the metabolic pathway which degrades excess phenylalanine.

The other substrates in the reaction are molecular oxygen and tetrahydrobiopterin. Tetrahydrobiopterin is a member of the group of redox biochemicals known as pteridines. PAH is the gene that encodes for phenylalanine hydroxylase.

Contents 1 Clinical significance 2 Related enzymes 3 Structure 4 External links 5 References 6 Further reading

Mutations in phenylalanine hydroxylase which result in lower activity are the cause of the disease phenylketonuria, or PKU.

Phenylalanine hydroxylase is closely related to two other enzymes:

• tryptophan hydroxylase (EC number 1.14.16.4), which controls levels of serotonin in the brain and the gastrointestinal tract
• tyrosine hydroxylase (EC number 1.14.16.2), which controls levels of dopamine, epinephrine, and norepinephrine in the brain and the adrenal medulla.

The three enzymes are homologous, that is, are thought to have evolved from the same ancient hydroxylase.

Phenylalanine hydroxylase is a tetramer composed of two dimers, that is, composed of two complexes of two subunits each. Each subunit is in turn composed of three domains, a regulatory domain, a catalytic domain, and a tetramerization domain.

• The regulatory domain is composed of the approximately 115 amino acids nearest the amino terminal of the subunit.

• The catalytic domain is composed of the next approximately 300 amino acids, and is responsible for all of the catalytic activity of the enzyme.

• The tetramerization domain consists of the remaining amino acids and through the formation of a coiled-coil arrangement of amino acids, holds the tetrameric structure of the holoenzyme together with a leucine zipper.

Phenylalanine hydroxylase contains one bound iron atom per subunit which is necessary for catalytic activity.

• The Phenylalanine Hydroxylase Protein

v • d • e Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)
1.14.11 - 2-oxoglutarate	Prolyl hydroxylase - Lysyl hydroxylase
1.14.13 - NADH or NADPH	Flavin-containing monooxygenase - Nitric oxide synthase - Cholesterol 7 alpha-hydroxylase - Methane monooxygenase - 3A4 -51A1
1.14.14 - reduced flavin or flavoprotein	19A1 - 2D6 - 2E1
1.14.15 - reduced iron-sulfur protein	11B1 - 11B2 - 11A1
1.14.16 - reduced pteridine	Phenylalanine hydroxylase - Tyrosine hydroxylase - Tryptophan hydroxylase
1.14.17 - reduced ascorbate	Dopamine beta hydroxylase
1.14.18-19 - other	Tyrosinase - Stearoyl-CoA desaturase-1
1.14.99 - miscellaneous	Cyclooxygenase - Heme oxygenase (HMOX1) - Squalene monooxygenase - 17A1 - 21A2

v • d • e Amino acid metabolism enzymes
phenylalanine→tyrosine→fumarate→TCA	Phenylalanine hydroxylase - Tyrosine aminotransferase - 4-Hydroxyphenylpyruvate dioxygenase - Homogentisate 1,2-dioxygenase - Fumarylacetoacetate hydrolase
tyrosine→dopamine→epinephrine	Tyrosine hydroxylase - Aromatic L-amino acid decarboxylase - Dopamine beta hydroxylase - Phenylethanolamine N-methyltransferase
leucine→HMG-CoA (keto)	Branched-chain alpha-keto acid dehydrogenase complex - Isovaleryl coenzyme A dehydrogenase - Methylcrotonyl-CoA carboxylase
isoleucine/valine→propionyl-CoA	Branched-chain alpha-keto acid dehydrogenase complex
methionine→cysteine→propionyl-CoA	Methionine adenosyltransferase - Adenosylhomocysteinase - (or MTR) - Cystathionine beta synthase - Cystathionine gamma-lyase
propionyl-CoA→succinyl-CoA→TCA	Propionyl-CoA carboxylase - Methylmalonyl-CoA mutase
serine→glycine	Serine hydroxymethyltransferase
histidine	to histamine: Histidine decarboxylase - to glutamate: Histidine ammonia-lyase - Urocanate hydratase - Formiminotransferase cyclodeaminase
tryptophan→serotonin→melatonin	Tryptophan hydroxylase - Aromatic L-amino acid decarboxylase - 5-hydroxyindole-O-methyltransferase
asparagine→aspartate→oxaloacetate→TCA	Asparaginase/Asparagine synthetase - Aspartate transaminase
glutamate	Glutaminase - Glutamate decarboxylase
lysine→keto	Saccharopine dehydrogenase
other	Tyrosinase