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Q8IWU9 (TPH2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 112. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tryptophan 5-hydroxylase 2

EC=1.14.16.4
Alternative name(s):
Neuronal tryptophan hydroxylase
Tryptophan 5-monooxygenase 2
Gene names
Name:TPH2
Synonyms:NTPH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length490 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Catalytic activity

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

Cofactor

Fe2+ ion By similarity.

Pathway

Aromatic compound metabolism; serotonin biosynthesis; serotonin from L-tryptophan: step 1/2.

Tissue specificity

Brain specific.

Involvement in disease

Major depressive disorder (MDD) [MIM:608516]: A 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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Attention deficit-hyperactivity disorder 7 (ADHD7) [MIM:613003]: A neurobehavioral developmental disorder primarily characterized by the coexistence of attentional problems and hyperactivity, with each behavior occurring infrequently alone.
Note: 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. Ref.7

Sequence similarities

Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

Contains 1 ACT domain.

Biophysicochemical properties

Kinetic parameters:

KM=41.3 µM for L-tryptophan Ref.4

Vmax=833 nmol/min/mg enzyme

RNA editing

Edited at positions 433, 441 and 468.
Modulates the kinetic properties of both isoforms. Ref.5

Ontologies

Keywords
   Biological processSerotonin biosynthesis
   Coding sequence diversityAlternative splicing
Polymorphism
RNA editing
   DiseaseDisease mutation
   LigandIron
Metal-binding
   Molecular functionMonooxygenase
Oxidoreductase
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaromatic amino acid family metabolic process

Inferred from electronic annotation. Source: InterPro

cellular nitrogen compound metabolic process

Traceable author statement. Source: Reactome

cellular response to lithium ion

Inferred from electronic annotation. Source: Ensembl

circadian rhythm

Inferred from electronic annotation. Source: Ensembl

indolalkylamine biosynthetic process

Traceable author statement. Source: Reactome

response to activity

Inferred from electronic annotation. Source: Ensembl

response to calcium ion

Inferred from electronic annotation. Source: Ensembl

response to estrogen

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from electronic annotation. Source: Ensembl

response to nutrient levels

Inferred from electronic annotation. Source: Ensembl

serotonin biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

neuron projection

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionamino acid binding

Inferred from electronic annotation. Source: InterPro

iron ion binding

Inferred from electronic annotation. Source: InterPro

tryptophan 5-monooxygenase activity

Inferred from electronic annotation. Source: UniProtKB-EC

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform a (identifier: Q8IWU9-1)

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.
Isoform b (identifier: Q8IWU9-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 490490Tryptophan 5-hydroxylase 2
PRO_0000205574

Regions

Domain65 – 14076ACT

Sites

Metal binding3181Iron By similarity
Metal binding3231Iron By similarity
Metal binding3631Iron By similarity

Natural variations

Alternative sequence1471E → GKE in isoform b.
VSP_040971
Natural variant361L → P The property of the variant is indistinguishable from the wild-type. Ref.8
VAR_058938
Natural variant361L → V The property of the variant is indistinguishable from the wild-type. Ref.8
Corresponds to variant rs34115267 [ dbSNP | Ensembl ].
VAR_058939
Natural variant411S → Y The property of the variant is indistinguishable from the wild-type. Ref.8
Corresponds to variant rs78162420 [ dbSNP | Ensembl ].
VAR_058940
Natural variant551R → C The property of the variant is indistinguishable from the wild-type. Ref.8
Corresponds to variant rs75558144 [ dbSNP | Ensembl ].
VAR_058941
Natural variant2061P → 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. Ref.4 Ref.8
Corresponds to variant rs17110563 [ dbSNP | Ensembl ].
VAR_046136
Natural variant3031R → W in ADHD7; has severely reduced solubility and is completely inactive; loss of function may lead to a reduced serotonin synthesis which in turn makes the mutation carriers susceptible to ADHD and possibly other psychiatric disorders. Ref.7 Ref.8
VAR_058942
Natural variant3281A → V Moderate loss-of-function observed manifested via stability and solubility effect. Ref.8
Corresponds to variant rs2887147 [ dbSNP | Ensembl ].
VAR_058943
Natural variant4331R → G in RNA edited version.
VAR_065019
Natural variant4411R → H May be due to a rare RNA editing event; functional polymorphism linked with susceptibility to major depressive disorder; 80% loss of function; decreases solubility; decreases thermal stability; reduces catalytic activity. Ref.4 Ref.6 Ref.8
VAR_026749
Natural variant4681Q → R in RNA edited version.
VAR_065020
Natural variant4791D → E Moderate loss-of-function observed manifested via stability and solubility effect. Ref.8
Corresponds to variant rs7488262 [ dbSNP | Ensembl ].
VAR_058944

Experimental info

Sequence conflict531S → N in AAI14500. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform a [UniParc].

Last modified March 1, 2003. Version 1.
Checksum: 753645E6E0CE430B

FASTA49056,057
        10         20         30         40         50         60 
MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK GSSKREAATE 

        70         80         90        100        110        120 
SGKTAVVFSL KNEVGGLVKA LRLFQEKRVN MVHIESRKSR RRSSEVEIFV DCECGKTEFN 

       130        140        150        160        170        180 
ELIQLLKFQT TIVTLNPPEN IWTEEEELED VPWFPRKISE LDKCSHRVLM YGSELDADHP 

       190        200        210        220        230        240 
GFKDNVYRQR RKYFVDVAMG YKYGQPIPRV EYTEEETKTW GVVFRELSKL YPTHACREYL 

       250        260        270        280        290        300 
KNFPLLTKYC GYREDNVPQL EDVSMFLKER SGFTVRPVAG YLSPRDFLAG LAYRVFHCTQ 

       310        320        330        340        350        360 
YIRHGSDPLY TPEPDTCHEL LGHVPLLADP KFAQFSQEIG LASLGASDED VQKLATCYFF 

       370        380        390        400        410        420 
TIEFGLCKQE GQLRAYGAGL LSSIGELKHA LSDKACVKAF DPKTTCLQEC LITTFQEAYF 

       430        440        450        460        470        480 
VSESFEEAKE KMRDFAKSIT RPFSVYFNPY TQSIEILKDT RSIENVVQDL RSDLNTVCDA 

       490 
LNKMNQYLGI 

« Hide

Isoform b [UniParc].

Checksum: 5B90CB629F9F6DD6
Show »

FASTA49256,242

References

« Hide 'large scale' references
[1]"Synthesis of serotonin by a second tryptophan hydroxylase isoform."
Walther D.J., Peter J.-U., Bashammakh S., Hortnagl H., Voits M., Fink H., Bader M.
Science 299:76-76(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
[2]"The finished DNA sequence of human chromosome 12."
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. expand/collapse author list , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A.
Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
[4]"Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder."
Cichon S., Winge I., Mattheisen M., Georgi A., Karpushova A., Freudenberg J., Freudenberg-Hua Y., Babadjanova G., Van Den Bogaert A., Abramova L.I., Kapiletti S., Knappskog P.M., McKinney J., Maier W., Jamra R.A., Schulze T.G., Schumacher J., Propping P. expand/collapse author list , Rietschel M., Haavik J., Noethen M.M.
Hum. Mol. Genet. 17:87-97(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: BIOPHYSICOCHEMICAL PROPERTIES, VARIANT SER-206, CHARACTERIZATION OF VARIANTS SER-206 AND HIS-441.
[5]"Alternative splicing and extensive RNA editing of human TPH2 transcripts."
Grohmann M., Hammer P., Walther M., Paulmann N., Buttner A., Eisenmenger W., Baghai T.C., Schule C., Rupprecht R., Bader M., Bondy B., Zill P., Priller J., Walther D.J.
PLoS ONE 5:E8956-E8956(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORMS A AND B), RNA EDITING OF POSITIONS 433; 441 AND 468.
Tissue: Brain.
[6]"Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression."
Zhang X., Gainetdinov R.R., Beaulieu J.-M., Sotnikova T.D., Burch L.H., Williams R.B., Schwartz D.A., Krishnan K.R.R., Caron M.G.
Neuron 45:11-16(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HIS-441, CHARACTERIZATION OF VARIANT HIS-441.
[7]"A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder."
McKinney J., Johansson S., Halmoy A., Dramsdahl M., Winge I., Knappskog P.M., Haavik J.
Mol. Psychiatry 13:365-367(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ADHD7 TRP-303.
[8]"Functional properties of missense variants of human tryptophan hydroxylase 2."
McKinney J.A., Turel B., Winge I., Knappskog P.M., Haavik J.
Hum. Mutat. 30:787-794(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS VAL-36; PRO-36; TYR-41; CYS-55; SER-206; TRP-303; VAL-328; HIS-441 AND GLU-479.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY098914 mRNA. Translation: AAM28946.1.
AC090109 Genomic DNA. No translation available.
BC114499 mRNA. Translation: AAI14500.1.
CCDSCCDS31859.1. [Q8IWU9-1]
RefSeqNP_775489.2. NM_173353.3. [Q8IWU9-1]
UniGeneHs.736576.

3D structure databases

ProteinModelPortalQ8IWU9.
SMRQ8IWU9. Positions 48-484.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ8IWU9. 1 interaction.
MINTMINT-7997360.
STRING9606.ENSP00000329093.

Chemistry

BindingDBQ8IWU9.
ChEMBLCHEMBL5433.
DrugBankDB00150. L-Tryptophan.
GuidetoPHARMACOLOGY1242.

PTM databases

PhosphoSiteQ8IWU9.

Polymorphism databases

DMDM30580625.

Proteomic databases

PaxDbQ8IWU9.
PRIDEQ8IWU9.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000333850; ENSP00000329093; ENSG00000139287. [Q8IWU9-1]
GeneID121278.
KEGGhsa:121278.
UCSCuc001swy.2. human. [Q8IWU9-1]

Organism-specific databases

CTD121278.
GeneCardsGC12P072284.
HGNCHGNC:20692. TPH2.
HPAHPA046274.
MIM607478. gene.
608516. phenotype.
613003. phenotype.
neXtProtNX_Q8IWU9.
PharmGKBPA128747823.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG3186.
HOGENOMHOG000233373.
HOVERGENHBG006841.
KOK00502.
OMAEDVSMFL.
OrthoDBEOG7KM5T1.
PhylomeDBQ8IWU9.
TreeFamTF313327.

Enzyme and pathway databases

BioCycMetaCyc:HS06603-MONOMER.
ReactomeREACT_111217. Metabolism.
SABIO-RKQ8IWU9.
UniPathwayUPA00846; UER00799.

Gene expression databases

ArrayExpressQ8IWU9.
BgeeQ8IWU9.
CleanExHS_TPH2.
GenevestigatorQ8IWU9.

Family and domain databases

Gene3D1.10.800.10. 1 hit.
InterProIPR002912. 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]
PANTHERPTHR11473. PTHR11473. 1 hit.
PfamPF01842. ACT. 1 hit.
PF00351. Biopterin_H. 1 hit.
[Graphical view]
PIRSFPIRSF000336. TH. 1 hit.
PRINTSPR00372. FYWHYDRXLASE.
SUPFAMSSF56534. SSF56534. 1 hit.
TIGRFAMsTIGR01270. Trp_5_monoox. 1 hit.
PROSITEPS51671. ACT. 1 hit.
PS00367. BH4_AAA_HYDROXYL_1. 1 hit.
PS51410. BH4_AAA_HYDROXYL_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiTPH2.
GenomeRNAi121278.
NextBio80710.
PROQ8IWU9.
SOURCESearch...

Entry information

Entry nameTPH2_HUMAN
AccessionPrimary (citable) accession number: Q8IWU9
Secondary accession number(s): A6NGA4, Q14CB0
Entry history
Integrated into UniProtKB/Swiss-Prot: May 9, 2003
Last sequence update: March 1, 2003
Last modified: July 9, 2014
This is version 112 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM