TPH2 (tryptophan 5-hydroxylase 2; neuronal tryptophan hydroxylase; EC 1.14.16.4) is a soluble, tetrameric, biopterin-dependent aromatic amino acid hydroxylase and the neuronal paralog of TPH1. It catalyzes the rate-limiting step of serotonin (5-hydroxytryptamine) biosynthesis: the tetrahydrobiopterin (BH4)-, ferrous-iron- and O2-dependent hydroxylation of L-tryptophan to 5-hydroxy-L-tryptophan (5-HTP), which is subsequently decarboxylated by aromatic L-amino acid decarboxylase to yield serotonin (step 1 of 2). The enzyme comprises an N-terminal ACT regulatory domain, a central iron-containing catalytic domain, and a C-terminal leucine-zipper tetramerization domain. TPH2 is brain-specific and is expressed in serotonergic neurons of the brainstem raphe nuclei, where it produces the central-nervous-system serotonin pool throughout life; it is also present in enteric neurons of the gut. Because it is rate-limiting for CNS serotonin, loss-of-function variants of TPH2 are studied in the context of susceptibility to mood and psychiatric disorders including major depressive disorder, bipolar disorder and attention-deficit/hyperactivity disorder.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043005 neuron projection | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation of neuron-projection localization across the TPH family. TPH2 is a brain-specific enzyme expressed in serotonergic neurons and, like other neuronal serotonin-synthesis machinery, is active in neuron projections (nerve terminals), where serotonin is produced and released. This is a correct, biologically appropriate location, though the soluble enzyme is fundamentally cytosolic (the cytosol annotation captures the primary compartment). Accept as a valid non-core location. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt TISSUE SPECIFICITY: Brain specific. |
| GO:0004510 tryptophan 5-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation of the defining catalytic activity of the TPH family. This is TPH2's core molecular function and is directly supported by experiment for the human enzyme (see the IDA annotation from PMID:37608910) as well as by the UniProt catalytic-activity and EC 1.14.16.4 records. Accept as core. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt RecName: Full=Tryptophan 5-hydroxylase 2; file:human/TPH2/TPH2-uniprot.txt Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tryptophan + O2 |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IEA) generalization. TPH2 is a monooxygenase (it incorporates one atom of molecular oxygen into L-tryptophan, releasing the other as water), so this parent term is correct. It is, however, a broad ancestor of the specific and experimentally supported tryptophan 5-monooxygenase activity (GO:0004510); keep as a true but non-core generalization rather than removing it. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt AltName: Full=Neuronal tryptophan hydroxylase; file:human/TPH2/TPH2-uniprot.txt Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tryptophan + O2 |
| GO:0004510 tryptophan 5-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assignment of the specific catalytic activity via InterPro/RHEA/EC mapping (EC 1.14.16.4, RHEA:16709). This is the correct core molecular function and is redundant with, and corroborated by, the experimental IDA and the phylogenetic IBA for the same term. Accept the gene's own correct core activity. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt EC=1.14.16.4 {ECO:0000269|PubMed:37608910}; file:human/TPH2/TPH2-uniprot.txt = 5-hydroxy-L-tryptophan + (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8- |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IEA) assignment of iron ion binding. TPH2 is a non-heme iron enzyme whose catalytic center coordinates a mononuclear ferrous iron (Fe2+) required for hydroxylation; UniProt records Fe(2+) as cofactor and three iron-coordinating binding residues. This is a correct core molecular function. Accept. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000250}; file:human/TPH2/TPH2-uniprot.txt ligand="Fe cation" |
| GO:0009072 aromatic amino acid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IEA) generalization. TPH2 acts on the aromatic amino acid L-tryptophan, so this parent process term is technically correct. It is, however, a broad ancestor of the specific serotonin biosynthetic process (GO:0042427), which better captures the enzyme's actual biological role. Keep as a true but non-core generalization. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt PATHWAY: Aromatic compound metabolism; serotonin biosynthesis; |
| GO:0016714 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IEA) generalization to the pterin-dependent monooxygenase parent class. This exactly describes the mechanistic class of TPH2 (a reduced-pteridine/BH4-dependent oxidoreductase that incorporates one oxygen atom), so it is correct, but it is a broad ancestor of the specific tryptophan 5-monooxygenase activity (GO:0004510). Keep as a true but non-core mechanistic generalization. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tryptophan + O2 |
| GO:0042427 serotonin biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assignment via UniPathway mapping. TPH2 catalyzes the first and rate-limiting step of serotonin biosynthesis (L-tryptophan -> 5-HTP), so this is the gene's core biological process. Accept the gene's own correct core process. Supporting Evidence: file:human/TPH2/TPH2-uniprot.txt serotonin from L-tryptophan: step 1/2. Reactome:R-HSA-209828 The first and rate limiting step in serotonin (5-HT) biosynthesis is catalyzed |
| GO:0004510 tryptophan 5-monooxygenase activity | IDA PMID:37608910 The A328 V/E (rs2887147) polymorphisms in human tryptophan h... | ACCEPT | Summary: Direct experimental (IDA) demonstration of tryptophan 5-monooxygenase activity for the human enzyme. Carkaci-Salli et al. purified recombinant full-length hTPH2 and measured its enzymatic conversion of L-tryptophan (with BH4 and O2), establishing wild-type kinetic parameters (KM, Vmax) and showing that the A328E variant abolishes and A328V reduces this activity. This is the strongest evidence for the core molecular function. Accept as core. Supporting Evidence: PMID:37608910 The recombinant full-length enzyme PMID:37608910 A328E had no measurable enzyme activity |
| GO:0005829 cytosol | TAS Reactome:R-HSA-209828 | ACCEPT | Summary: Traceable author statement (TAS, Reactome) localizing the tryptophan-hydroxylation reaction to the cytosol. TPH2 is a soluble tetrameric enzyme and the serotonin-synthesis reaction occurs in the neuronal cytoplasm/cytosol, consistent with the cytosolic nature of the aromatic amino acid hydroxylases. Accept as the primary subcellular location. Supporting Evidence: Reactome:R-HSA-209828 the hydroxylation of L-tryptophan to 5-hydroxytryptophan |
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