Q8IWU9 (TPH2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

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]. Defects in TPH2 are the cause of susceptibility to attention deficit-hyperactivity disorder type 7 (ADHD7) [MIM:613003]. ADHD is a neurobehavioral developmental disorder and is primarily characterized by the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone. Note=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.8
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.5 Vmax=833 nmol/min/mg enzyme
RNA editing	Edited at positions 433, 441 and 468. Modulates the kinetic properties of both isoforms. Ref.6

Ontologies

Keywords
Biological process	Serotonin biosynthesis
Coding sequence diversity	Alternative splicing Polymorphism RNA editing
Disease	Disease mutation
Ligand	Iron Metal-binding
Molecular function	Monooxygenase Oxidoreductase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	aromatic amino acid family metabolic process Inferred from electronic annotation. Source: InterPro hormone biosynthetic process Traceable author statement. Source: Reactome serotonin biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	amino acid binding Inferred from electronic annotation. Source: InterPro iron ion binding Inferred from electronic annotation. Source: InterPro tryptophan 5-monooxygenase activity Traceable author statement. Source: Reactome
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 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.4
	Modified residue	392	1	Phosphoserine Ref.4
Natural variations
	Alternative sequence	147	1	E → GKE in isoform b.		VSP_040971
	Natural variant	36	1	L → P The property of the variant is indistinguishable from the wild-type. Ref.9		VAR_058938
	Natural variant	36	1	L → V The property of the variant is indistinguishable from the wild-type. Ref.9 Corresponds to variant rs34115267 [ dbSNP | Ensembl ].		VAR_058939
	Natural variant	41	1	S → Y The property of the variant is indistinguishable from the wild-type. Ref.9		VAR_058940
	Natural variant	55	1	R → C The property of the variant is indistinguishable from the wild-type. Ref.9		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. Ref.5 Ref.9 Corresponds to variant rs17110563 [ dbSNP | Ensembl ].		VAR_046136
	Natural variant	303	1	R → 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.8 Ref.9		VAR_058942
	Natural variant	328	1	A → V Moderate loss-of-function observed manifested via stability and solubility effect. Ref.9 Corresponds to variant rs2887147 [ dbSNP | Ensembl ].		VAR_058943
	Natural variant	433	1	R → G in RNA edited version.		VAR_065019
	Natural variant	441	1	R → 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.5 Ref.7 Ref.9		VAR_026749
	Natural variant	468	1	Q → R in RNA edited version.		VAR_065020
	Natural variant	479	1	D → E Moderate loss-of-function observed manifested via stability and solubility effect. Ref.9 Corresponds to variant rs7488262 [ dbSNP | Ensembl ].		VAR_058944
Experimental info
	Sequence conflict	53	1	S → N in AAI14500. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform a [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
	Isoform b [UniParc]. Checksum: 5B90CB629F9F6DD6	FASTA	492	56,242
	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 IWTEEEGKEL EDVPWFPRKI SELDKCSHRV LMYGSELDAD 190 200 210 220 230 240 HPGFKDNVYR QRRKYFVDVA MGYKYGQPIP RVEYTEEETK TWGVVFRELS KLYPTHACRE 250 260 270 280 290 300 YLKNFPLLTK YCGYREDNVP QLEDVSMFLK ERSGFTVRPV AGYLSPRDFL AGLAYRVFHC 310 320 330 340 350 360 TQYIRHGSDP LYTPEPDTCH ELLGHVPLLA DPKFAQFSQE IGLASLGASD EDVQKLATCY 370 380 390 400 410 420 FFTIEFGLCK QEGQLRAYGA GLLSSIGELK HALSDKACVK AFDPKTTCLQ ECLITTFQEA 430 440 450 460 470 480 YFVSESFEEA KEKMRDFAKS ITRPFSVYFN PYTQSIEILK DTRSIENVVQ DLRSDLNTVC 490 DALNKMNQYL GI

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] (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. , 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]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
[4]	"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. Tissue: Embryonic kidney.
[5]	"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.
[6]	"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: 20126463] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORMS A AND B), RNA EDITING OF POSITIONS 433; 441 AND 468. Tissue: Brain.
[7]	"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.
[8]	"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: 18347598] [Abstract] Cited for: VARIANT ADHD7 TRP-303.
[9]	"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. BC114499 mRNA. Translation: AAI14500.1.
IPI	IPI00783677. IPI01009748.
RefSeq	NP_775489.2. NM_173353.3.
UniGene	Hs.376337.
3D structure databases
ProteinModelPortal	Q8IWU9.
SMR	Q8IWU9. Positions 20-484.
ModBase	Search...
Protein-protein interaction databases
STRING	Q8IWU9.
PTM databases
PhosphoSite	Q8IWU9.
Polymorphism databases
DMDM	30580625.
Proteomic databases
PRIDE	Q8IWU9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000333850; ENSP00000329093; ENSG00000139287.
GeneID	121278.
KEGG	hsa:121278.
UCSC	uc009zrw.1. human.
Organism-specific databases
CTD	121278.
GeneCards	GC12P072284.
H-InvDB	HIX0022703.
HGNC	HGNC:20692. TPH2.
HPA	HPA046274.
MIM	607478. gene. 608516. phenotype. 613003. phenotype.
neXtProt	NX_Q8IWU9.
PharmGKB	PA128747823.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG15939.
GeneTree	ENSGT00390000010268.
HOVERGEN	HBG006841.
OrthoDB	EOG4S7JPZ.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism.
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.
KO	K00502.
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.
SUPFAM	SSF56534. Aaa_hydroxylase. 1 hit.
TIGRFAMs	TIGR01270. Trp_5_monoox. 1 hit.
PROSITE	PS00367. BH4_AAA_HYDROXYL_1. 1 hit. PS51410. BH4_AAA_HYDROXYL_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
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, Q14CB0

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 9, 2003
Last sequence update:	March 1, 2003
Last modified:	January 25, 2012
This is version 86 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.