TPH2

Tryptophan hydroxylase 2 (TPH2) is an isozyme of tryptophan hydroxylase found in vertebrates. In humans, TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain. Until the discovery of TPH2 in 2003,^[5] serotonin levels in the central nervous system were believed to be regulated by serotonin synthesis in peripheral tissues, in which tryptophan hydroxylase is the dominant form.^[6]

TPH2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4V06
Identifiers
Aliases	TPH2, ADHD7, NTPH, tryptophan hydroxylase 2
External IDs	OMIM: 607478; MGI: 2651811; HomoloGene: 27831; GeneCards: TPH2; OMA:TPH2 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q21.1 Start 71,938,845 bp[1] End 72,186,618 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 D2 Start 114,914,546 bp[2] End 115,020,927 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte testicle gonad superior vestibular nucleus islet of Langerhans sural nerve prefrontal cortex anterior pituitary white blood cell monocyte Top expressed in dorsal tegmental nucleus central gray substance of midbrain zygote secondary oocyte primary oocyte embryo enteric nervous system sensory ganglion trigeminal ganglion pontine nuclei More reference expression data BioGPS n/a
Gene ontology Molecular function iron ion binding metal ion binding monooxygenase activity tryptophan 5-monooxygenase activity 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 oxidoreductase activity Cellular component cytosol neuron projection Biological process cellular response to lithium ion response to glucocorticoid response to activity serotonin biosynthetic process response to estrogen response to calcium ion aromatic amino acid family metabolic process response to nutrient levels circadian rhythm indolalkylamine biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 121278 216343 Ensembl ENSG00000139287 ENSMUSG00000006764 UniProt Q8IWU9 Q8CGV2 RefSeq (mRNA) NM_173353 NM_173391 RefSeq (protein) NP_775489 NP_775567 Location (UCSC) Chr 12: 71.94 – 72.19 Mb Chr 10: 114.91 – 115.02 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Tryptophan hydroxylase (TPH; EC 1.14.16.4) is the rate-limiting enzyme in the synthesis of serotonin (5-hydroxytryptamine, or 5HT). 5HT is causally involved in numerous central nervous activities, and it has several functions in peripheral tissues, including the maintenance of vascular tone and gut motility.[supplied by OMIM]^[7]

Disabling this enzyme with drugs (especially p-chlorophenylalanine aka PCPA and Fenclonine) has allowed researchers to investigate the effects of very low serotonin levels on humans and others animals, and by extension, gain insights into the functions of serotonin systems more broadly (such as hypersexuality in rodents as well as increased aggression and hypersexuality cats following PCPA administration^[8]). In rat brain, administration of a single PCPA injection resulted in the lowest level of serotonin production occurring on day 2 and returning to control values on day 7.^[9] Drugs such as MDMA^[10] and methamphetamine^[11] have been shown to lower levels of this enzyme which may result in periods of low serotonin levels following drug use. In a study investigating the effects of Fenclonine on humans, the greatly lowered serotonin levels were associated with "fatigue, dizziness, nausea, uneasiness [anxiety], fullness in the head [a feeling of pressure in the head] paresthesias [a pricking, pins-and-needles, burning, and/or aching sensation--typically the limbs], headache, and constipation".^[12]

See also

• Tryptophan hydroxylase
• TPH1

References

1. GRCh38: Ensembl release 89: ENSG00000139287 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000006764 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (January 2003). "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science. 299 (5603): 76. doi:10.1126/science.1078197. PMID 12511643. S2CID 7095712.
6. Zill P, Büttner A, Eisenmenger W, Möller HJ, Ackenheil M, Bondy B (2005). "Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study". Journal of Psychiatric Research. 41 (1–2): 168–173. doi:10.1016/j.jpsychires.2005.05.004. PMID 16023677.
7. "Entrez Gene: TPH2 tryptophan hydroxylase 2".
8. Ferguson J, Henriksen S, Cohen H, Mitchell G, Barchas J, Dement W (April 1970). ""Hypersexuality" and behavioral changes in cats caused by administration of p-chlorophenylalanine". Science. 168 (3930): 499–501. Bibcode:1970Sci...168..499F. doi:10.1126/science.168.3930.499. PMID 5461688. S2CID 16691506.
9. Richard F, Sanne JL, Bourde O, Weissman D, Ehret M, Cash C, et al. (December 1990). "Variation of tryptophan-5-hydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration. I. A model to study the turnover of the enzymatic protein". Brain Research. 536 (1–2): 41–45. doi:10.1016/0006-8993(90)90006-w. PMID 2150773. S2CID 12214077.
10. Bonkale WL, Austin MC (July 2008). "3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus". Neuroscience. 155 (1): 270–276. doi:10.1016/j.neuroscience.2008.03.086. PMC 2505057. PMID 18515011.
11. Hotchkiss AJ, Gibb JW (August 1980). "Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain". The Journal of Pharmacology and Experimental Therapeutics. 214 (2): 257–262. PMID 6104722.
12. Cremata VY, Koe BK (May 1968). "Clinical and biochemical effects of fenclonine: a serotonin depletor". Diseases of the Nervous System. 29 (5): Suppl:147–Suppl:152. PMID 5673619. Retrieved 2 July 2022.

Further reading

• Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (January 2003). "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science. 299 (5603): 76. doi:10.1126/science.1078197. PMID 12511643. S2CID 7095712.
• Walther DJ, Bader M (November 2003). "A unique central tryptophan hydroxylase isoform". Biochemical Pharmacology. 66 (9): 1673–1680. doi:10.1016/S0006-2952(03)00556-2. PMID 14563478.
• Zill P, Baghai TC, Zwanzger P, Schüle C, Eser D, Rupprecht R, et al. (November 2004). "SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression". Molecular Psychiatry. 9 (11): 1030–1036. doi:10.1038/sj.mp.4001525. PMID 15124006.
• Breidenthal SE, White DJ, Glatt CE (June 2004). "Identification of genetic variants in the neuronal form of tryptophan hydroxylase (TPH2)". Psychiatric Genetics. 14 (2): 69–72. doi:10.1097/01.ypg.0000107929.32051.58. PMID 15167691. S2CID 21842482.
• De Luca V, Mueller DJ, Tharmalingam S, King N, Kennedy JL (October 2004). "Analysis of the novel TPH2 gene in bipolar disorder and suicidality". Molecular Psychiatry. 9 (10): 896–897. doi:10.1038/sj.mp.4001531. PMID 15197398.
• Harvey M, Shink E, Tremblay M, Gagné B, Raymond C, Labbé M, et al. (November 2004). "Support for the involvement of TPH2 gene in affective disorders". Molecular Psychiatry. 9 (11): 980–981. doi:10.1038/sj.mp.4001557. PMID 15263906.
• Zill P, Büttner A, Eisenmenger W, Möller HJ, Bondy B, Ackenheil M (October 2004). "Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims". Biological Psychiatry. 56 (8): 581–586. doi:10.1016/j.biopsych.2004.07.015. PMID 15476687. S2CID 24630985.
• Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, et al. (January 2005). "Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression". Neuron. 45 (1): 11–16. doi:10.1016/j.neuron.2004.12.014. PMID 15629698. S2CID 15865069.
• Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A, et al. (May 2005). "Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2)". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 135B (1): 42–46. doi:10.1002/ajmg.b.30168. PMID 15768392. S2CID 32184220.
• Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z (October 2005). "Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD". Molecular Psychiatry. 10 (10): 944–949. doi:10.1038/sj.mp.4001698. PMID 15940290. S2CID 2460069.
• Shamir A, Shaltiel G, Levi I, Belmaker RH, Agam G (2005). "Postmortem parietal cortex TPH2 expression is not altered in schizophrenic, unipolar-depressed, and bipolar patients vs control subjects". Journal of Molecular Neuroscience. 26 (1): 33–37. doi:10.1385/JMN:26:1:033. PMID 15968084. S2CID 20701904.
• Brown SM, Peet E, Manuck SB, Williamson DE, Dahl RE, Ferrell RE, Hariri AR (September 2005). "A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity". Molecular Psychiatry. 10 (9): 884–8, 805. doi:10.1038/sj.mp.4001716. PMID 16044172.
• Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, et al. (December 2005). "Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder". Molecular Psychiatry. 10 (12): 1126–1132. doi:10.1038/sj.mp.4001734. PMID 16116490.
• Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP (November 2005). "Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation". Journal of Neural Transmission. 112 (11): 1479–1485. doi:10.1007/s00702-005-0391-4. PMID 16245070. S2CID 24755144.
• Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P, et al. (July 2006). "The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder". Journal of Psychopharmacology. 20 (4): 547–552. doi:10.1177/0269881106059704. PMID 16401665. S2CID 20360040.
• De Luca V, Hlousek D, Likhodi O, Van Tol HH, Kennedy JL, Wong AH (February 2006). "The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses". Genes, Brain and Behavior. 5 (1): 107–110. doi:10.1111/j.1601-183X.2005.00182.x. PMID 16436194. S2CID 1739158.
• Delorme R, Durand CM, Betancur C, Wagner M, Ruhrmann S, Grabe HJ, et al. (July 2006). "No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects" (PDF). Biological Psychiatry. 60 (2): 202–203. doi:10.1016/j.biopsych.2005.12.014. PMID 16581035. S2CID 221881.
• Carkaci-Salli N, Flanagan JM, Martz MK, Salli U, Walther DJ, Bader M, Vrana KE (September 2006). "Functional domains of human tryptophan hydroxylase 2 (hTPH2)". The Journal of Biological Chemistry. 281 (38): 28105–28112. doi:10.1074/jbc.M602817200. PMID 16864580.