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).
last edited


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

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens


Inborn Errors of Metabolism (IEM) Pathways Rare Diseases


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

Pathway Ontology: phenylalanine degradation pathway tetrahydrobiopterin metabolic pathway Segawa syndrome pathway phenylketonuria pathway dopa responsive dystonia pathway


Label Type Compact Identifier 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
PTPS GeneProduct uniprot:Q03393 AKA 6-pyruvoyl-tetrahydropterin synthase
GTPCH GeneProduct uniprot:P30793 aka GTP cyclohydrolase I
DNAJC12 GeneProduct ncbigene:56521 co-chaperone of PAH
SR GeneProduct wikidata:Q15331000 sepiapterin reductase
SR GeneProduct wikidata:Q15331000 sepiapterin reductase
DNAJC12 GeneProduct ncbigene:56521 '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'
DHPR Protein wikidata:Q21145902 dihydropteridine reductase
DHFR Protein wikidata:Q417149 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
PNMT Protein uniprot:P11086 AKA phenylethanolamine-N-methyltransferase
CR Protein eccode: AKA carbonyl reductase
PAH Protein uniprot:P00439 AKA phenylalanine hydroxylase
TH Protein wikidata:Q420766 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 wikidata:Q1145916 carbonyl reductase
PAH Protein wikidata:Q420604 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
CR Protein eccode: AKA carbonyl reductase
AR Protein eccode: AKA aldose reductase
AADC Protein wikidata:Q421186 aromatic l-amino acid decarboxylase
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


  1. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Springer; 2014. 867 p. Available from: OpenLibrary Worldcat
  2. Hyland K. Neurochemistry and defects of biogenic amine neurotransmitter metabolism. J Inherit Metab Dis. 1999 Jun;22(4):353–63. PubMed Europe PMC Scholia
  3. Pearl PL, Wallis DD, Gibson KM. Pediatric neurotransmitter diseases. Curr Neurol Neurosci Rep. 2004 Mar;4(2):147–52. PubMed Europe PMC Scholia
  4. Kusmierska K, Jansen EEW, Jakobs C, Szymanska K, Malunowicz E, Meilei D, et al. Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S5-10. PubMed Europe PMC Scholia
  5. Crabtree MJ, Channon KM. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide. 2011 Aug 1;25(2):81–8. PubMed Europe PMC Scholia
  6. Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Thöny B, Shen N, et al. Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. Am J Hum Genet. 2017 Feb 2;100(2):257–66. PubMed Europe PMC Scholia
  7. Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment. Neuropediatrics. 2019 Feb;50(1):2–14. PubMed Europe PMC Scholia
  8. Jung-Kc K, Himmelreich N, Prestegård KS, Shi T-JS, Scherer T, Ying M, et al. Phenylalanine hydroxylase variants interact with the co-chaperone DNAJC12. Hum Mutat. 2019 Apr;40(4):483–94. PubMed Europe PMC Scholia
  9. Cho H-U, Kim S, Sim J, Yang S, An H, Nam M-H, et al. Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis. Exp Mol Med. 2021 Jul;53(7):1148–58. PubMed Europe PMC Scholia