Reviewed, UniProtKB/Swiss-Prot Q8IWU9 (TPH2_HUMAN)

Names and origin

Protein names

Recommended name:
    Tryptophan 5-hydroxylase 2
    EC=1.14.16.4
Alternative name(s):
    Tryptophan 5-monooxygenase 2
    Neuronal tryptophan hydroxylase

Gene names

Name:	TPH2
Synonyms:	NTPH

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	490 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Genetic variation in TPH2 may influence susceptibility to major depressive disorder (MDD) [MIM:608516].
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 Vmax=833 nmol/min/mg enzyme

Ontologies

Keywords
Biological process	Serotonin biosynthesis
Coding sequence diversity	Polymorphism
Ligand	Iron Metal-binding
Molecular function	Monooxygenase Oxidoreductase
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	aromatic amino acid family metabolic process Inferred from electronic annotation. Source: InterPro oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW serotonin biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	amino acid binding Inferred from electronic annotation. Source: InterPro iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW tryptophan 5-monooxygenase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 490	490	Tryptophan 5-hydroxylase 2		PRO_0000205574
Regions
	Domain	64 – 136	73	ACT
Sites
	Metal binding	318	1	Iron By similarity
	Metal binding	323	1	Iron By similarity
	Metal binding	363	1	Iron By similarity
Amino acid modifications
	Modified residue	382	1	Phosphoserine Ref.3
	Modified residue	392	1	Phosphoserine Ref.3
Natural variations
	Natural variant	36	1	L → P The property of the variant is indistinguishable from the wild-type. Ref.6		VAR_058938
	Natural variant	36	1	L → V The property of the variant is indistinguishable from the wild-type. dbSNP rs34115267. Ref.6		VAR_058939
	Natural variant	41	1	S → Y The property of the variant is indistinguishable from the wild-type. Ref.6		VAR_058940
	Natural variant	55	1	R → C The property of the variant is indistinguishable from the wild-type. Ref.6		VAR_058941
	Natural variant	206	1	P → 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. dbSNP rs17110563. Ref.6 Ref.4		VAR_046136
	Natural variant	303	1	R → W Has severely reduced solubility and is completely inactive. Ref.6		VAR_058942
	Natural variant	328	1	A → V Moderate loss-of-function observed manifested via stability and solubility effect. dbSNP rs2887147. Ref.6		VAR_058943
	Natural variant	441	1	R → H Polymorphism linked with susceptibility to major depressive disorder; 80% loss of function; decreases solubility; decreases thermal stability; reduces catalytic activity. Ref.6 Ref.4 Ref.5		VAR_026749
	Natural variant	479	1	D → E Moderate loss-of-function observed manifested via stability and solubility effect. dbSNP rs7488262. Ref.6		VAR_058944

Sequences

	Sequence		Length	Mass (Da)
	Q8IWU9-1 [UniParc]. Last modified March 1, 2003. Version 1. Checksum: 753645E6E0CE430B	FASTA	490	56,057
	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

References

	« Hide 'large scale' referencesShow '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: 12511643] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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. , 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: 16541075] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry." Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A. Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007) [PubMed: 17287340] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-382 AND SER-392, MASS SPECTROMETRY.
[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. , Rietschel M., Haavik J., Noethen M.M. Hum. Mol. Genet. 17:87-97(2008) [PubMed: 17905754] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, VARIANT SER-206, CHARACTERIZATION OF VARIANTS SER-206 AND HIS-441.
[5]	"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: 15629698] [Abstract] Cited for: VARIANT HIS-441, CHARACTERIZATION OF VARIANT HIS-441.
[6]	"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: 19319927] [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.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY098914 mRNA. Translation: AAM28946.1. AC090109 Genomic DNA. No translation available.
IPI	IPI00854884.
RefSeq	NP_775489.2.
UniGene	Hs.376337
3D structure databases
SMR	Q8IWU9. Positions 58-129, 151-484.
ModBase	Search...
Protein-protein interaction databases
STRING	Q8IWU9.
PTM databases
PhosphoSite	Q8IWU9.
Proteomic databases
PRIDE	Q8IWU9.
Genome annotation databases
Ensembl	ENST00000333850; ENSP00000329093; ENSG00000139287; Homo sapiens. [Genome view]
GeneID	121278.
KEGG	hsa:121278.
UCSC	uc009zrw.1. human.
Organism-specific databases
CTD	121278.
GeneCards	GC12P070618.
H-InvDB	HIX0022703.
HGNC	HGNC:20692. TPH2.
MIM	607478. gene. 608516. phenotype.
PharmGKB	PA128747823.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG15939.
HOVERGEN	Q8IWU9.
Enzyme and pathway databases
BRENDA	1.14.16.4. 247.
Gene expression databases
ArrayExpress	Q8IWU9.
Bgee	Q8IWU9.
CleanEx	HS_TPH2.
Genevestigator	Q8IWU9.
GermOnline	ENSG00000139287. Homo sapiens.
Family and domain databases
InterPro	IPR002912. ACT_bd. 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]
Gene3D	G3DSA:1.10.800.10. Aaa_hydroxylase. 1 hit.
PANTHER	PTHR11473. Aaa_hydroxylase. 1 hit.
Pfam	PF01842. ACT. 1 hit. PF00351. Biopterin_H. 1 hit. [Graphical view]
PIRSF	PIRSF000336. TH. 1 hit.
PRINTS	PR00372. FYWHYDRXLASE.
TIGRFAMs	TIGR01270. Trp_5_monoox. 1 hit.
PROSITE	PS00367. BIOPTERIN_HYDROXYL. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00150. L-Tryptophan.
NextBio	80710.
SOURCE	Search...

Entry information

Entry name

TPH2_HUMAN

Accession

Primary (citable) accession number: Q8IWU9
Secondary accession number(s): A6NGA4

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 9, 2003
Last sequence update:	March 1, 2003
Last modified:	February 9, 2010
This is version 67 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.