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).ce4b06ea8dihydropteridine reductaseAKA 3-ortho-methyldopa (3-OMD)dihydrofolate reductaseAKA 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]DihydrobiopterinAKA tetrahydropterin, 5,6,7,8-tetrahydrobiopterinea8bdbAKA dopamine
β-hydroxylase6-pyruvoyl tetrahydropterin, 6PPH4aka GTP cyclohydrolase Isepiapterin reductase, gene SPRNecessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM).AKA phenylethanolamine-N-methyltransferaseAKA carbonyl reductaseb06AKA pterin-4a-carbinolamineAKA phenylalanine hydroxylaseAKA 6-pyruvoyl-tetrahydropterin synthasehomovanillic acidaka 7,8-dihydroneopterin 3'-triphosphate, dihydroneopterin triphosphate, dihydroneopterin-PPPtyrosine hydroxylaseAKA monoamine oxidase5-hydroxyindoleacetic acidAKA 6-lactoyltetrahydropterin (1′-oxoTHP) [PMID:1913029].b06AKA aldose reductaseb06"Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A." Source: https://en.wikipedia.org/wiki/Monoamine_oxidasetryptophan hydroxylaseAKA pterin-4a-carbinolamine dehydratase7,8-dihydrobiopterincarbonyl reductase, Wikidata:Q1145916phenylalanine-4-hydroxylaseAKA hydroxyindole O-methyltransferase, HIOMT (deprecated alias), N-Acetylserotonin O-methyltransferase, also known as ASMTco-chaperone of PAHsepiapterin reductase"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"AKA carbonyl reductaseb06AKA aldose reductaseb06aromatic l-amino acid decarboxylase; Wikidata: Q421186AKA monoamine oxidase"Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A." Source: https://en.wikipedia.org/wiki/Monoamine_oxidase"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_oxidaseAKA 3-methoxy-4-hydroxyphenylglycolAKA Vanillylmandelic acidNecessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM).Alternative PWbdbb06f99b92b06b92non-enzymatic, twodirectional [PMID:19130291]b06bdbf99b92ea8bdbea8bdbAlternative PWb06f99ea8bdbb92b92bdbbdbb92ea8bdbadebdbea8bdbb92b92adeadebbdf99b92f99f99f99b92b92b92b9221550412PubMedSynthesis and recycling of tetrahydrobiopterin in endothelial function and vascular diseaseNitric Oxide .2011Mark J CrabtreeKeith M Channonaromatic L-amino acid decarboxylase deficiencyDOID:0090123Diseasephenylalanine degradation pathwayPW:0001288Pathway Ontologymegaloblastic anemiaDOID:13382DiseaseBh4-deficient hyperphenylalaninemia ADOID:0090106Disease30372766PubMedInherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and TreatmentNeuropediatrics . 2019Heiko BrennenstuhlSabine Jung-KlawitterBirgit AssmannThomas Opladen14984687PubMedPediatric neurotransmitter diseasesCurr Neurol Neurosci Rep.2004Phillip L PearlDenise D WallisK Michael GibsonBH4-deficient hyperphenylalaninemia BDOID:0112225Disease10407772PubMedNeurochemistry and defects of biogenic amine neurotransmitter metabolismJ Inherit Metab Dis .1999K Hyland30667134PubMedhenylalanine hydroxylase variants interact with the co- chaperone DNAJC12.Hum Mutat.2019Kunwar Jung-KcNastassja HimmelreichKarina S PrestegårdTie-Jun Sten ShiTanja SchererMing YingAna Jorge-FinniganBeat ThönyNenad BlauAurora Martinezdopa responsive dystonia pathwayPW:0002105Pathway Ontology34244591PubMedRedefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesisExp Mol Med . 2021Hyun-U ChoSunpil KimJeongeun SimSeulkee YangHeeyoung AnMin-Ho NamDong-Pyo JangC Justin Leedystonia 5DOID:0090043Diseasetetrahydrobiopterin metabolic pathwayPW:0000217Pathway OntologySegawa syndrome pathwayPW:0001612Pathway Ontology28132689PubMedBiallelic mutations in DNAJC12 cause hyperphenylal- aninemia, dystonia, and intellectual disabilityAm J Hum Genet.2017Yair AniksterTobias B HaackThierry VilbouxBen Pode-ShakkedBeat ThönyNan ShenVirginia GuaraniThomas MeissnerErtan MayatepekFriedrich K TrefzDina Marek-YagelAurora MartinezEdward L HuttlinJoao A PauloRiccardo BeruttiJean-François BenoistApolline ImbardImen DorbozGali HeimerYuval LandauLimor Ziv-StrasserMay Christine V MalicdanCorinne Gemperle-BritschgiKirsten CremerHartmut EngelsDavid MeiliIrene KellerRémy BruggmannTim M StromThomas MeitingerJames C MullikinGerard SchwartzBruria Ben-ZeevWilliam A GahlJ Wade HarperNenad BlauGeorg F HoffmannHolger ProkischThomas OpladenManuel Schiffsepiapterin reductase deficiencyDOID:0111168DiseasephenylketonuriaDOID:9281Disease19130291PubMedSepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-upJ Inherit Metab Dis .2009K KusmierskaE E W JansenC JakobsK SzymanskaE MalunowiczD MeileiB ThonyN BlauJ TryfonD RokickiE PronickaJ Sykut-Cegielskaphenylketonuria pathwayPW:0001805Pathway Ontology9783642403361ISBNPhysician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases'20149783642403361PubMedPhysician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases' Springer-Verlag Berlin Heidelberg Ed.42014Blau, NenadDuran, MarinusGibson, K. MichaelDionisi-Vici, Carlo