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).
Authors
Denise Slenter , Egon Willighagen , Irene Hemel , Daniela Digles , Josien Landman , Friederike Ehrhart , Finterly Hu , and Eric WeitzActivity
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Organisms
Homo sapiensCommunities
Inherited Metabolic Disorders (IMD) Pathways ONTOX Rare Diseases Serious Request 2024 - MetaKidsAnnotations
Disease Ontology
aromatic L-amino acid decarboxylase deficiency megaloblastic anemia BH4-deficient hyperphenylalaninemia A BH4-deficient hyperphenylalaninemia B dystonia 5 sepiapterin reductase deficiency phenylketonuriaPathway 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 | |
| MHPG | Metabolite | chebi:1576 | AKA 3-methoxy-4-hydroxyphenylglycol |
| Epinephrine | Metabolite | hmdb:HMDB00068 | |
| VMA | Metabolite | chebi:20106 | AKA Vanillylmandelic acid |
| 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 2.3.1.87), 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: https://en.wikipedia.org/wiki/Aralkylamine_N-acetyltransferase] |
| 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:1.1.1.184 | 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:1.4.3.4 | AKA monoamine oxidase |
| AR | Protein | eccode:1.1.1.21 | AKA aldose reductase |
| MAOA | Protein | uniprot:P21397 | 'Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A.' Source: https://en.wikipedia.org/wiki/Monoamine_oxidase |
| TPH | Protein | eccode:1.14.16.4 | tryptophan hydroxylase |
| PCD | Protein | eccode:4.2.1.96 | AKA pterin-4a-carbinolamine dehydratase |
| CR | Protein | eccode:1.1.1.184 | 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' |
| AADC | Protein | eccode:4.1.1.28 | aromatic l-amino acid decarboxylase; Wikidata: Q421186 |
| 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: https://en.wikipedia.org/wiki/Monoamine_oxidase |
References
- Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
- Neurochemistry and defects of biogenic amine neurotransmitter metabolism. Hyland K. J Inherit Metab Dis. 1999 Jun;22(4):353–63. PubMed Europe PMC Scholia
- Pediatric neurotransmitter diseases. Pearl PL, Wallis DD, Gibson KM. Curr Neurol Neurosci Rep. 2004 Mar;4(2):147–52. PubMed Europe PMC Scholia
- 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
- 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
- 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
- Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment. Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Neuropediatrics. 2019 Feb;50(1):2–14. PubMed Europe PMC Scholia
- 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
- 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