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). ce4 b06 ea8 dihydropteridine reductase AKA 3-ortho-methyldopa (3-OMD) dihydrofolate reductase 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] Dihydrobiopterin AKA tetrahydropterin, 5,6,7,8-tetrahydrobiopterin ea8 bdb AKA dopamine β-hydroxylase 6-pyruvoyl tetrahydropterin, 6PPH4 aka GTP cyclohydrolase I sepiapterin reductase, gene SPR Necessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM). AKA phenylethanolamine-N-methyltransferase AKA carbonyl reductase b06 AKA pterin-4a-carbinolamine AKA phenylalanine hydroxylase AKA 6-pyruvoyl-tetrahydropterin synthase homovanillic acid aka 7,8-dihydroneopterin 3'-triphosphate, dihydroneopterin triphosphate, dihydroneopterin-PPP tyrosine hydroxylase AKA monoamine oxidase 5-hydroxyindoleacetic acid AKA 6-lactoyltetrahydropterin (1′-oxoTHP) [PMID:1913029]. b06 AKA aldose reductase b06 "Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A." Source: https://en.wikipedia.org/wiki/Monoamine_oxidase tryptophan hydroxylase AKA pterin-4a-carbinolamine dehydratase 7,8-dihydrobiopterin carbonyl reductase, Wikidata:Q1145916 phenylalanine-4-hydroxylase AKA hydroxyindole O-methyltransferase, HIOMT (deprecated alias), N-Acetylserotonin O-methyltransferase, also known as ASMT co-chaperone of PAH sepiapterin 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 reductase b06 AKA aldose reductase b06 aromatic l-amino acid decarboxylase; Wikidata: Q421186 AKA 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_oxidase AKA 3-methoxy-4-hydroxyphenylglycol AKA Vanillylmandelic acid Necessary cofactor for enzymatic reaction (lead by enzyme catechol-O-methyltransferase) is s-adenosyl methionine (SAM). Alternative PW bdb b06 f99 b92 b06 b92 non-enzymatic, twodirectional [PMID:19130291] b06 bdb f99 b92 ea8 bdb ea8 bdb Alternative PW b06 f99 ea8 bdb b92 b92 bdb bdb b92 ea8 bdb ade bdb ea8 bdb b92 b92 ade ade bbd f99 b92 f99 f99 f99 b92 b92 b92 b92 "Sepiapterin synthase, ?" [PMID:21550412] DISEASE DISEASE aka Dystonia 5, segawa disease DISEASE DISEASE DISEASE aka Classic Phenylketonuria DISEASE DISEASE DISEASE DISEASE aka Segawa syndrome DISEASE DISEASE e14 DISEASE e14 Segawa syndrome pathway PW:0001612 Pathway Ontology phenylketonuria DOID:9281 Disease 9783642403361 ISBN Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases' 2014 9783642403361 PubMed Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases' Springer-Verlag Berlin Heidelberg Ed.4 2014 Blau, Nenad Duran, Marinus Gibson, K. Michael Dionisi-Vici, Carlo 10407772 PubMed Neurochemistry and defects of biogenic amine neurotransmitter metabolism J Inherit Metab Dis . 1999 K Hyland 30667134 PubMed henylalanine hydroxylase variants interact with the co-­ chaperone DNAJC12. Hum Mutat. 2019 Kunwar Jung-Kc Nastassja Himmelreich Karina S Prestegård Tie-Jun Sten Shi Tanja Scherer Ming Ying Ana Jorge-Finnigan Beat Thöny Nenad Blau Aurora Martinez aromatic L-amino acid decarboxylase deficiency DOID:0090123 Disease 14984687 PubMed Pediatric neurotransmitter diseases Curr Neurol Neurosci Rep. 2004 Phillip L Pearl Denise D Wallis K Michael Gibson phenylketonuria pathway PW:0001805 Pathway Ontology Bh4-deficient hyperphenylalaninemia A DOID:0090106 Disease dopa responsive dystonia pathway PW:0002105 Pathway Ontology 19130291 PubMed Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up J Inherit Metab Dis . 2009 K Kusmierska E E W Jansen C Jakobs K Szymanska E Malunowicz D Meilei B Thony N Blau J Tryfon D Rokicki E Pronicka J Sykut-Cegielska dystonia 5 DOID:0090043 Disease 28132689 PubMed Biallelic mutations in DNAJC12 cause hyperphenylal- aninemia, dystonia, and intellectual disability Am J Hum Genet. 2017 Yair Anikster Tobias B Haack Thierry Vilboux Ben Pode-Shakked Beat Thöny Nan Shen Virginia Guarani Thomas Meissner Ertan Mayatepek Friedrich K Trefz Dina Marek-Yagel Aurora Martinez Edward L Huttlin Joao A Paulo Riccardo Berutti Jean-François Benoist Apolline Imbard Imen Dorboz Gali Heimer Yuval Landau Limor Ziv-Strasser May Christine V Malicdan Corinne Gemperle-Britschgi Kirsten Cremer Hartmut Engels David Meili Irene Keller Rémy Bruggmann Tim M Strom Thomas Meitinger James C Mullikin Gerard Schwartz Bruria Ben-Zeev William A Gahl J Wade Harper Nenad Blau Georg F Hoffmann Holger Prokisch Thomas Opladen Manuel Schiff BH4-deficient hyperphenylalaninemia B DOID:0112225 Disease 30372766 PubMed Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment Neuropediatrics . 2019 Heiko Brennenstuhl Sabine Jung-Klawitter Birgit Assmann Thomas Opladen 21550412 PubMed Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease Nitric Oxide . 2011 Mark J Crabtree Keith M Channon megaloblastic anemia DOID:13382 Disease 34244591 PubMed Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis Exp Mol Med . 2021 Hyun-U Cho Sunpil Kim Jeongeun Sim Seulkee Yang Heeyoung An Min-Ho Nam Dong-Pyo Jang C Justin Lee phenylalanine degradation pathway PW:0001288 Pathway Ontology tetrahydrobiopterin metabolic pathway PW:0000217 Pathway Ontology sepiapterin reductase deficiency DOID:0111168 Disease