Biosynthesis and regeneration of tetrahydrobiopterin and catabolism of phenylalanine (WP4156)

Homo sapiens

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 Edition 5, Chapter 20 of the book of Blau (ISBN 9783030677268) (Ed.4 Chapter 1).


Denise Slenter , Egon Willighagen , Irene Hemel , Daniela Digles , Josien Landman , Friederike Ehrhart , Finterly Hu , and Eric Weitz


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Homo sapiens


Inherited Metabolic Disorders (IMD) Pathways Rare Diseases


Disease Ontology

aromatic L-amino acid decarboxylase deficiency megaloblastic anemia BH4-deficient hyperphenylalaninemia A BH4-deficient hyperphenylalaninemia B dystonia 5 sepiapterin reductase deficiency phenylketonuria

Pathway Ontology

phenylalanine degradation pathway dopa responsive dystonia pathway tetrahydrobiopterin metabolic pathway Segawa syndrome pathway phenylketonuria pathway


Label Type Compact URI Comment
3-OMD Metabolite chebi:82913 AKA 3-ortho-methyldopa (3-OMD)
Primapterin Metabolite wikidata:Q26261687
q-BH2 Metabolite chebi:43120 Dihydrobiopterin
BH4 Metabolite chebi:30436 AKA tetrahydropterin, 5,6,7,8-tetrahydrobiopterin
PTP Metabolite chebi:136564 6-pyruvoyl tetrahydropterin, 6PPH4
SAM Metabolite chebi:15414 Necessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM).
Phe Metabolite chebi:28044
norepinephrine Metabolite chebi:33569
Serotonin Metabolite chebi:28790
HO-BH4 Metabolite chebi:15642 AKA pterin-4a-carbinolamine
5-OH-Trp Metabolite chebi:58266
Dopamine Metabolite wikidata:Q170304
HVA Metabolite wikidata:Q903566 homovanillic acid
sepiapterin Metabolite wikidata:Q2271580
N-acetylserotonin Metabolite chebi:17697
Biopterin Metabolite wikidata:Q41793745
L-DOPA Metabolite wikidata:Q300989
NH2TP Metabolite chebi:58462 aka 7,8-dihydroneopterin 3'-triphosphate, dihydroneopterin triphosphate, dihydroneopterin-PPP
GTP Metabolite chebi:37565
5HIAA Metabolite hmdb:HMDB0000763 5-hydroxyindoleacetic acid
oxo-PH4 Metabolite pubchem.compound:135398702 AKA 6-lactoyltetrahydropterin (1′-oxoTHP) [PMID:1913029].
Phenyl-alanine Metabolite wikidata:Q170545
Neopterin Metabolite wikidata:Q908292
Trp Metabolite wikidata:Q181003
7,8-BH2 Metabolite wikidata:Q5276421 7,8-dihydrobiopterin
NADPH Metabolite wikidata:Q26841327
tyr Metabolite wikidata:Q188017
O2 Metabolite chebi:15379
O2 Metabolite chebi:15379
MHPG Metabolite chebi:1576 AKA 3-methoxy-4-hydroxyphenylglycol
Epinephrine Metabolite hmdb:HMDB00068
VMA Metabolite chebi:20106 AKA Vanillylmandelic acid
SAM Metabolite chebi:15414 Necessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM).
melatonin Metabolite chebi:16796
DHPR Protein uniprot:P09417 dihydropteridine reductase
DHFR Protein uniprot:P00374 dihydrofolate reductase
SNA Protein uniprot:Q16613 AKA serotonin N-acetylase; 'Aralkylamine N-acetyltransferase (AANAT) (EC, also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT); an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. ' Source:]
DBH Protein uniprot:P09172 AKA dopamine β-hydroxylase
GTPCH Protein uniprot:P30793 aka GTP cyclohydrolase I
SR Protein uniprot:P35270 sepiapterin reductase, gene SPR
PNMT Protein uniprot:P11086 AKA phenylethanolamine-N-methyltransferase
CR Protein eccode: AKA carbonyl reductase
PAH Protein uniprot:P00439 AKA phenylalanine hydroxylase
PTPS Protein uniprot:Q03393 AKA 6-pyruvoyl-tetrahydropterin synthase
TH Protein uniprot:P07101 tyrosine hydroxylase
MAO Protein eccode: AKA monoamine oxidase
AR Protein eccode: AKA aldose reductase
MAOA Protein uniprot:P21397 'Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A.' Source:
TPH Protein eccode: tryptophan hydroxylase
PCD Protein eccode: AKA pterin-4a-carbinolamine dehydratase
CR Protein eccode: carbonyl reductase, Wikidata:Q1145916
PAH Protein uniprot:P00439 phenylalanine-4-hydroxylase
COMT Protein uniprot:P21964
ASMT Protein uniprot:P46597 AKA hydroxyindole O-methyltransferase, HIOMT (deprecated alias), N-Acetylserotonin O-methyltransferase, also known as ASMT
DNAJC12 Protein uniprot:Q9UKB3 co-chaperone of PAH
SR Protein uniprot:P35270 sepiapterin reductase
DNAJC12 Protein uniprot:Q9UKB3 'DNAJC12 interacts with PAH, TH, and the TPHs, which indicates that DNAJC12 is a specific co-­chaperone for the aromatic amino acid hydroxylases that contributes to the maintenance of their intracellular stability'
CR Protein eccode: AKA carbonyl reductase
AR Protein eccode: AKA aldose reductase
AADC Protein eccode: aromatic l-amino acid decarboxylase; Wikidata: Q421186
MAO Protein eccode: AKA monoamine oxidase
MAOA Protein uniprot:P21397 'Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A.' Source:
MAOB Protein uniprot:P27338 'MAO-A and MAO-B were believed to metabolize dopamine, tyramine, and tryptamine; however, recent evidence suggests MAO-B may not be responsible for a significant amount of dopamine degradation.' Source:
COMT Protein uniprot:P21964


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  4. Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up. Kusmierska K, Jansen EEW, Jakobs C, Szymanska K, Malunowicz E, Meilei D, et al. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S5-10. PubMed Europe PMC Scholia
  5. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Crabtree MJ, Channon KM. Nitric Oxide. 2011 Aug 1;25(2):81–8. PubMed Europe PMC Scholia
  6. Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Thöny B, Shen N, et al. Am J Hum Genet. 2017 Feb 2;100(2):257–66. PubMed Europe PMC Scholia
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  8. Phenylalanine hydroxylase variants interact with the co-chaperone DNAJC12. Jung-Kc K, Himmelreich N, Prestegård KS, Shi TJS, Scherer T, Ying M, et al. Hum Mutat. 2019 Apr;40(4):483–94. PubMed Europe PMC Scholia
  9. Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis. Cho HU, Kim S, Sim J, Yang S, An H, Nam MH, et al. Exp Mol Med. 2021 Jul;53(7):1148–58. PubMed Europe PMC Scholia