Biosynthesis and regeneration of tetrahydrobiopterin and catabolism of phenylalanine (Homo sapiens)

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1Non-enzymaticGTP cyclohydrolase deficiencyPrimapterinPhePCDSerotoninDHFRPTPSNeopterinGTPCHPTPTrpTHBH4PAHDHPRNH2TPq-BH2TPHCRHO-BH45HIAABiopterin7,8-BH2HVAtyrPhenyl-alanineoxo-PH4SRAADCGTPDopamineL-DOPAsepiapterinO25-OH-TrpO2SRSRDopa-responsive dystonia6-pyruvoyl-tetrahydropterin synthase deficiencysepiapterin reductase deficiencyphenylalanine-4-hydroxylase deficiencydihydrofolate reductase deficiencydihydropteridine reductase deficiencypterin-4a-carbinolamine dehydratasen deficiencytyrosine hydroxylase deficiencyaromatic l-amino acid decarboxylase deficiencyDiseaseCatalysisPathwayStimulationProteinMetaboliteConversionConnection to diseaseLegendBiomarker


This pathway shows disorders related to phenylalanine and tetrahydrobiopterin (BH4) metabolism. Disorders resulting from an enzyme defect are highlighted in pink. Pathological metabolites used as specific markers are highlighted in purple. BH4 is a natural cofactor for PAH, tyrosine-3-hydroxylase, tryptophan-5-hydroxylase and nitric oxide synthase (NOS), where the latter two are key enzymes in the biosynthesis of the neurotransmitters dopamine and serotonin. This pathway was inspired by Chapter 1 of the book of Blau (ISBN 3642403360 (978-3642403361)).

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Ontology Terms



  1. Blau, Nenad, Duran, Marinus, Gibson, K. Michael, Dionisi-Vici, Carlo; ''Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases'''; , 2014


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121756view12:02, 3 March 2022DeSlAdded source for book ref.
120404view09:16, 30 November 2021Fehrhartboxed pathway node
119290view11:03, 23 June 2021FinterlyAdded ISBN for book citation
114490view12:55, 17 January 2021DeSlAdded small textual details
114393view16:13, 9 January 2021DeSlAdditional comment for THD (SEGAWA)
114392view16:11, 9 January 2021DeSlOntology Term : 'Segawa syndrome pathway' added !
114391view16:11, 9 January 2021DeSlUpdating OMIM ID for tyrosine hydroxylase deficiency.
114390view16:07, 9 January 2021DeSlOntology Term : 'dystonia 5' added !
114389view16:06, 9 January 2021DeSlOntology Term : 'sepiapterin reductase deficiency' added !
114388view16:06, 9 January 2021DeSlOntology Term : 'megaloblastic anemia' added !
114387view16:04, 9 January 2021DeSlOntology Term : 'PW:0000013' removed !
114386view16:03, 9 January 2021DeSlMore updates for readability of full PW.
114385view15:59, 9 January 2021DeSlVisual updates for readability
114384view15:56, 9 January 2021DeSlAdded legend
111782view13:40, 7 September 2020DeSlUpdated Ec ID for tryptophan hydroxylase
111627view06:16, 31 August 2020EgonwModified description
111626view06:15, 31 August 2020EgonwModified title
108075view11:44, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
106780view13:26, 17 September 2019MaintBotHMDB identifier normalization
104867view11:54, 21 June 2019Josienlandmancorrected two OMIM references
104403view14:54, 23 May 2019IreneHemelAdded Rhea, ChEBI and Uniprot IDs
104397view14:22, 23 May 2019IreneHemelChanged interactions to graphical lines for diseases
104072view13:37, 2 May 2019DdiglesAdded rhea IDs for TPH and PCD reactions, added/modified ChEBI IDs for molecules in these reactions.
104018view17:35, 25 April 2019IreneHemelModified description
98949view12:20, 17 October 2018DeSlModified description
98253view09:47, 15 August 2018DeSlModified description
98248view09:16, 15 August 2018DeSlChanged all disease nodes to textlabels, with linkouts to OMIM
96451view09:30, 15 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
94865view15:19, 10 October 2017DeSlAdded lit. ref
94864view15:16, 10 October 2017DeSlOntology Term : 'Bh4-deficient hyperphenylalaninemia A' added !
94863view15:15, 10 October 2017DeSlOntology Term : 'aromatic L-amino acid decarboxylase deficiency' added !
94862view15:14, 10 October 2017DeSlOntology Term : 'phenylalanine degradation pathway' added !
94861view15:14, 10 October 2017DeSlOntology Term : 'tetrahydrobiopterin metabolic pathway' added !
94860view15:13, 10 October 2017DeSladded ID for AADC
94859view15:11, 10 October 2017DeSlAdded OMIM IDs for diseases
94858view15:06, 10 October 2017DeSlChanged database to Wikidata for several nodes
94857view15:03, 10 October 2017DeSlModified description
94856view15:02, 10 October 2017DeSlModified description
94855view14:56, 10 October 2017DeSlNew pathway

External references


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NameTypeDatabase referenceComment
5-OH-TrpMetaboliteCHEBI:58266 (ChEBI)
5HIAAMetaboliteHMDB0000763 (HMDB) 5-hydroxyindoleacetic acid
7,8-BH2MetaboliteQ5276421 (Wikidata) 7,8-dihydrobiopterin
AADCProteinQ421186 (Wikidata) aromatic l-amino acid decarboxylase
BH4MetaboliteCHEBI:30436 (ChEBI) tetrahydropterin
BiopterinMetaboliteQ41793745 (Wikidata)
CRProteinQ1145916 (Wikidata) carbonyl reductase
DHFRProteinQ417149 (Wikidata) dihydrofolate reductase
DHPRProteinQ21145902 (Wikidata) dihydropteridine reductase
DopamineMetaboliteQ170304 (Wikidata)
GTPMetaboliteCHEBI:37565 (ChEBI)
GTPCHGeneProductP30793 (Uniprot-TrEMBL) GTP cyclohydrolase I
HO-BH4MetaboliteCHEBI:15642 (ChEBI)
HVAMetaboliteQ903566 (Wikidata) homovanillic acid
L-DOPAMetaboliteQ300989 (Wikidata)
NH2TPMetaboliteCHEBI:58462 (ChEBI) aka 7,8-dihydroneopterin 3'-triphosphate
NeopterinMetaboliteQ908292 (Wikidata)
O2MetaboliteCHEBI:15379 (ChEBI)
PAHProteinQ420604 (Wikidata) phenylalanine-4-hydroxylase
PCDProtein4.2.1.96 (Enzyme Nomenclature) pterin-4a-carbinolamine dehydratase
PTPMetaboliteCHEBI:136564 (ChEBI) 6-pyruvoyl tetrahydropterin
PTPSGeneProductQ03393 (Uniprot-TrEMBL) 6-pyruvoyl-tetrahydropterin synthase
PheMetaboliteCHEBI:28044 (ChEBI)
Phenyl-alanineMetaboliteQ170545 (Wikidata)
PrimapterinMetaboliteQ26261687 (Wikidata)
SRGeneProductQ15331000 (Wikidata) sepiapterin reductase
SerotoninMetaboliteCHEBI:28790 (ChEBI)
THProteinQ420766 (Wikidata) tyrosine hydroxylase
TPHProtein1.14.16.4 (Enzyme Nomenclature) tryptophan hydroxylase
TrpMetaboliteQ181003 (Wikidata)
q-BH2MetaboliteCHEBI:43120 (ChEBI) Dihydrobiopterin
sepiapterinMetaboliteQ2271580 (Wikidata)
tyrMetaboliteQ188017 (Wikidata)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
GTPNH2TPmim-conversion17474 (Rhea)
NH2TPPTPmim-conversion22049 (Rhea)
PCDmim-catalysisRHEA:11920 (Rhea)
TPHmim-catalysisRHEA:16709 (Rhea)
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