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Protein

Tryptophan 5-hydroxylase 2

Gene

TPH2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalytic activityi

L-tryptophan + tetrahydrobiopterin + O2 = 5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin.

Cofactori

Fe2+By similarity

Kineticsi

  1. KM=41.3 µM for L-tryptophan1 Publication
  1. Vmax=833 nmol/min/mg enzyme1 Publication

Pathwayi: serotonin biosynthesis

This protein is involved in step 1 of the subpathway that synthesizes serotonin from L-tryptophan.
Proteins known to be involved in the 2 steps of the subpathway in this organism are:
  1. Tryptophan 5-hydroxylase 2 (TPH2), Tryptophan 5-hydroxylase 1 (TPH1)
  2. no protein annotated in this organism
This subpathway is part of the pathway serotonin biosynthesis, which is itself part of Aromatic compound metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes serotonin from L-tryptophan, the pathway serotonin biosynthesis and in Aromatic compound metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi318IronBy similarity1
Metal bindingi323IronBy similarity1
Metal bindingi363IronBy similarity1

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Monooxygenase, Oxidoreductase

Keywords - Biological processi

Serotonin biosynthesis

Keywords - Ligandi

Iron, Metal-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS06603-MONOMER.
ZFISH:HS06603-MONOMER.
BRENDAi1.14.16.4. 2681.
ReactomeiR-HSA-209931. Serotonin and melatonin biosynthesis.
SABIO-RKQ8IWU9.
SIGNORiQ8IWU9.
UniPathwayiUPA00846; UER00799.

Names & Taxonomyi

Protein namesi
Recommended name:
Tryptophan 5-hydroxylase 2 (EC:1.14.16.4)
Alternative name(s):
Neuronal tryptophan hydroxylase
Tryptophan 5-monooxygenase 2
Gene namesi
Name:TPH2
Synonyms:NTPH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:20692. TPH2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Major depressive disorder (MDD)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA common psychiatric disorder. It is a complex trait characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning.
See also OMIM:608516
Attention deficit-hyperactivity disorder 7 (ADHD7)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry. Naturally occurring variants of TPH2 with impaired enzyme activity could cause deficiency of serotonin production and result in an increased risk of developing behavioral disorders.
Disease descriptionA neurobehavioral developmental disorder primarily characterized by the coexistence of attentional problems and hyperactivity, with each behavior occurring infrequently alone.
See also OMIM:613003
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_058942303R → W in ADHD7; has severely reduced solubility; is completely inactive; loss of function may lead to a reduced serotonin synthesis. 2 PublicationsCorresponds to variant rs120074176dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi121278.
MalaCardsiTPH2.
MIMi608516. phenotype.
613003. phenotype.
OpenTargetsiENSG00000139287.
PharmGKBiPA128747823.

Chemistry databases

ChEMBLiCHEMBL5433.
DrugBankiDB00150. L-Tryptophan.

Polymorphism and mutation databases

BioMutaiTPH2.
DMDMi30580625.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002055741 – 490Tryptophan 5-hydroxylase 2Add BLAST490

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei19PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ8IWU9.
PeptideAtlasiQ8IWU9.
PRIDEiQ8IWU9.

PTM databases

iPTMnetiQ8IWU9.
PhosphoSitePlusiQ8IWU9.

Expressioni

Tissue specificityi

Brain specific.

Gene expression databases

BgeeiENSG00000139287.
CleanExiHS_TPH2.
GenevisibleiQ8IWU9. HS.

Organism-specific databases

HPAiHPA046274.

Interactioni

Protein-protein interaction databases

BioGridi125720. 2 interactors.
IntActiQ8IWU9. 1 interactor.
MINTiMINT-7997360.
STRINGi9606.ENSP00000329093.

Chemistry databases

BindingDBiQ8IWU9.

Structurei

Secondary structure

1490
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi158 – 161Combined sources4
Helixi162 – 165Combined sources4
Beta strandi168 – 171Combined sources4
Turni180 – 183Combined sources4
Helixi185 – 199Combined sources15
Helixi214 – 228Combined sources15
Helixi231 – 234Combined sources4
Helixi237 – 249Combined sources13
Helixi260 – 270Combined sources11
Beta strandi274 – 277Combined sources4
Beta strandi279 – 282Combined sources4
Helixi284 – 291Combined sources8
Turni292 – 294Combined sources3
Beta strandi295 – 298Combined sources4
Helixi316 – 322Combined sources7
Helixi324 – 327Combined sources4
Helixi330 – 343Combined sources14
Helixi348 – 359Combined sources12
Turni360 – 364Combined sources5
Beta strandi365 – 369Combined sources5
Beta strandi372 – 375Combined sources4
Helixi378 – 382Combined sources5
Helixi384 – 390Combined sources7
Beta strandi392 – 395Combined sources4
Beta strandi397 – 399Combined sources3
Helixi402 – 405Combined sources4
Beta strandi412 – 414Combined sources3
Beta strandi419 – 423Combined sources5
Helixi425 – 435Combined sources11
Turni436 – 438Combined sources3
Beta strandi442 – 448Combined sources7
Turni449 – 452Combined sources4
Beta strandi453 – 457Combined sources5
Helixi460 – 488Combined sources29

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4V06X-ray2.63A/B148-490[»]
ProteinModelPortaliQ8IWU9.
SMRiQ8IWU9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini65 – 140ACTPROSITE-ProRule annotationAdd BLAST76

Sequence similaritiesi

Contains 1 ACT domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3820. Eukaryota.
COG3186. LUCA.
GeneTreeiENSGT00390000010268.
HOGENOMiHOG000233373.
HOVERGENiHBG006841.
InParanoidiQ8IWU9.
KOiK00502.
OMAiKNDDKGN.
OrthoDBiEOG091G05MZ.
PhylomeDBiQ8IWU9.
TreeFamiTF313327.

Family and domain databases

Gene3Di1.10.800.10. 1 hit.
InterProiIPR002912. ACT_dom.
IPR001273. ArAA_hydroxylase.
IPR018301. ArAA_hydroxylase_Fe/CU_BS.
IPR019774. Aromatic-AA_hydroxylase_C.
IPR005963. Trp_5_mOase.
IPR019773. Tyrosine_3-monooxygenase-like.
[Graphical view]
PANTHERiPTHR11473. PTHR11473. 1 hit.
PfamiPF00351. Biopterin_H. 1 hit.
[Graphical view]
PIRSFiPIRSF000336. TH. 1 hit.
PRINTSiPR00372. FYWHYDRXLASE.
SUPFAMiSSF56534. SSF56534. 1 hit.
TIGRFAMsiTIGR01270. Trp_5_monoox. 1 hit.
PROSITEiPS51671. ACT. 1 hit.
PS00367. BH4_AAA_HYDROXYL_1. 1 hit.
PS51410. BH4_AAA_HYDROXYL_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform a (identifier: Q8IWU9-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK
60 70 80 90 100
GSSKREAATE SGKTAVVFSL KNEVGGLVKA LRLFQEKRVN MVHIESRKSR
110 120 130 140 150
RRSSEVEIFV DCECGKTEFN ELIQLLKFQT TIVTLNPPEN IWTEEEELED
160 170 180 190 200
VPWFPRKISE LDKCSHRVLM YGSELDADHP GFKDNVYRQR RKYFVDVAMG
210 220 230 240 250
YKYGQPIPRV EYTEEETKTW GVVFRELSKL YPTHACREYL KNFPLLTKYC
260 270 280 290 300
GYREDNVPQL EDVSMFLKER SGFTVRPVAG YLSPRDFLAG LAYRVFHCTQ
310 320 330 340 350
YIRHGSDPLY TPEPDTCHEL LGHVPLLADP KFAQFSQEIG LASLGASDED
360 370 380 390 400
VQKLATCYFF TIEFGLCKQE GQLRAYGAGL LSSIGELKHA LSDKACVKAF
410 420 430 440 450
DPKTTCLQEC LITTFQEAYF VSESFEEAKE KMRDFAKSIT RPFSVYFNPY
460 470 480 490
TQSIEILKDT RSIENVVQDL RSDLNTVCDA LNKMNQYLGI
Length:490
Mass (Da):56,057
Last modified:March 1, 2003 - v1
Checksum:i753645E6E0CE430B
GO
Isoform b (identifier: Q8IWU9-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     147-147: E → GKE

Show »
Length:492
Mass (Da):56,242
Checksum:i5B90CB629F9F6DD6
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti53S → N in AAI14500 (PubMed:15489334).Curated1

RNA editingi

Edited at positions 433, 441 and 468.1 Publication
Modulates the kinetic properties of both isoforms.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05893836L → P The property of the variant is indistinguishable from the wild-type. 1 PublicationCorresponds to variant rs199775778dbSNPEnsembl.1
Natural variantiVAR_05893936L → V The property of the variant is indistinguishable from the wild-type. 1 PublicationCorresponds to variant rs34115267dbSNPEnsembl.1
Natural variantiVAR_05894041S → Y The property of the variant is indistinguishable from the wild-type. 1 PublicationCorresponds to variant rs78162420dbSNPEnsembl.1
Natural variantiVAR_05894155R → C The property of the variant is indistinguishable from the wild-type. 1 PublicationCorresponds to variant rs75558144dbSNPEnsembl.1
Natural variantiVAR_046136206P → S May be associated with susceptibility to bipolar affective disorder; decreases solubility; decreases thermal stability; catalytic activity as the wild type; moderate loss-of-function observed manifested via stability and solubility effect. 2 PublicationsCorresponds to variant rs17110563dbSNPEnsembl.1
Natural variantiVAR_058942303R → W in ADHD7; has severely reduced solubility; is completely inactive; loss of function may lead to a reduced serotonin synthesis. 2 PublicationsCorresponds to variant rs120074176dbSNPEnsembl.1
Natural variantiVAR_058943328A → V Moderate loss-of-function observed manifested via stability and solubility effect. 1 PublicationCorresponds to variant rs2887147dbSNPEnsembl.1
Natural variantiVAR_065019433R → G in RNA edited version. 1
Natural variantiVAR_026749441R → H Functional polymorphism linked with susceptibility to major depressive disorder; may be due to a rare RNA editing event; 80% loss of function; decreases solubility; decreases thermal stability; reduces catalytic activity. 3 PublicationsCorresponds to variant rs120074175dbSNPEnsembl.1
Natural variantiVAR_065020468Q → R in RNA edited version. 1
Natural variantiVAR_058944479D → E Moderate loss-of-function observed manifested via stability and solubility effect. 1 PublicationCorresponds to variant rs7488262dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_040971147E → GKE in isoform b. Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY098914 mRNA. Translation: AAM28946.1.
AC090109 Genomic DNA. No translation available.
BC114499 mRNA. Translation: AAI14500.1.
CCDSiCCDS31859.1. [Q8IWU9-1]
RefSeqiNP_775489.2. NM_173353.3. [Q8IWU9-1]
UniGeneiHs.736576.

Genome annotation databases

EnsembliENST00000333850; ENSP00000329093; ENSG00000139287. [Q8IWU9-1]
GeneIDi121278.
KEGGihsa:121278.
UCSCiuc009zrw.1. human. [Q8IWU9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism, RNA editing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY098914 mRNA. Translation: AAM28946.1.
AC090109 Genomic DNA. No translation available.
BC114499 mRNA. Translation: AAI14500.1.
CCDSiCCDS31859.1. [Q8IWU9-1]
RefSeqiNP_775489.2. NM_173353.3. [Q8IWU9-1]
UniGeneiHs.736576.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4V06X-ray2.63A/B148-490[»]
ProteinModelPortaliQ8IWU9.
SMRiQ8IWU9.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi125720. 2 interactors.
IntActiQ8IWU9. 1 interactor.
MINTiMINT-7997360.
STRINGi9606.ENSP00000329093.

Chemistry databases

BindingDBiQ8IWU9.
ChEMBLiCHEMBL5433.
DrugBankiDB00150. L-Tryptophan.

PTM databases

iPTMnetiQ8IWU9.
PhosphoSitePlusiQ8IWU9.

Polymorphism and mutation databases

BioMutaiTPH2.
DMDMi30580625.

Proteomic databases

PaxDbiQ8IWU9.
PeptideAtlasiQ8IWU9.
PRIDEiQ8IWU9.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000333850; ENSP00000329093; ENSG00000139287. [Q8IWU9-1]
GeneIDi121278.
KEGGihsa:121278.
UCSCiuc009zrw.1. human. [Q8IWU9-1]

Organism-specific databases

CTDi121278.
DisGeNETi121278.
GeneCardsiTPH2.
HGNCiHGNC:20692. TPH2.
HPAiHPA046274.
MalaCardsiTPH2.
MIMi607478. gene.
608516. phenotype.
613003. phenotype.
neXtProtiNX_Q8IWU9.
OpenTargetsiENSG00000139287.
PharmGKBiPA128747823.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3820. Eukaryota.
COG3186. LUCA.
GeneTreeiENSGT00390000010268.
HOGENOMiHOG000233373.
HOVERGENiHBG006841.
InParanoidiQ8IWU9.
KOiK00502.
OMAiKNDDKGN.
OrthoDBiEOG091G05MZ.
PhylomeDBiQ8IWU9.
TreeFamiTF313327.

Enzyme and pathway databases

UniPathwayiUPA00846; UER00799.
BioCyciMetaCyc:HS06603-MONOMER.
ZFISH:HS06603-MONOMER.
BRENDAi1.14.16.4. 2681.
ReactomeiR-HSA-209931. Serotonin and melatonin biosynthesis.
SABIO-RKQ8IWU9.
SIGNORiQ8IWU9.

Miscellaneous databases

GeneWikiiTPH2.
GenomeRNAii121278.
PROiQ8IWU9.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000139287.
CleanExiHS_TPH2.
GenevisibleiQ8IWU9. HS.

Family and domain databases

Gene3Di1.10.800.10. 1 hit.
InterProiIPR002912. ACT_dom.
IPR001273. ArAA_hydroxylase.
IPR018301. ArAA_hydroxylase_Fe/CU_BS.
IPR019774. Aromatic-AA_hydroxylase_C.
IPR005963. Trp_5_mOase.
IPR019773. Tyrosine_3-monooxygenase-like.
[Graphical view]
PANTHERiPTHR11473. PTHR11473. 1 hit.
PfamiPF00351. Biopterin_H. 1 hit.
[Graphical view]
PIRSFiPIRSF000336. TH. 1 hit.
PRINTSiPR00372. FYWHYDRXLASE.
SUPFAMiSSF56534. SSF56534. 1 hit.
TIGRFAMsiTIGR01270. Trp_5_monoox. 1 hit.
PROSITEiPS51671. ACT. 1 hit.
PS00367. BH4_AAA_HYDROXYL_1. 1 hit.
PS51410. BH4_AAA_HYDROXYL_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTPH2_HUMAN
AccessioniPrimary (citable) accession number: Q8IWU9
Secondary accession number(s): A6NGA4, Q14CB0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 9, 2003
Last sequence update: March 1, 2003
Last modified: November 2, 2016
This is version 134 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.