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Gene Review

TPH1  -  tryptophan hydroxylase 1

Homo sapiens

Synonyms: TPH, TPRH, TRPH, Tryptophan 5-hydroxylase 1, Tryptophan 5-monooxygenase 1
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Disease relevance of TPH1


Psychiatry related information on TPH1


High impact information on TPH1

  • The crystal structure of a complex containing deoxy CpG and a terpyridine platinum compound (TPH) shows a DNA double helical fragment with TPH intercalated between two Watson-Crick GC base pairs [11].
  • BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin [12].
  • RESULTS: There was a significant association between TPH genotypes and manic-depressive illness [13].
  • Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior [13].
  • RESULTS: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration [14].

Chemical compound and disease context of TPH1

  • Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes [8].
  • In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores [15].
  • We showed in human melanoma cells tryptophan hydroxylase (TPH) and hydroxyindole methyltransferase genes expression with the sequential enzymatic activities of TPH, serotonin (Ser) N-acetyltransferase and hydroxyindole methyltransferase [16].
  • The aim of this study was to investigate the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders [17].

Biological context of TPH1

  • Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04) [18].
  • Both enzymes are phosphorylated by cAMP-dependent protein kinase A. TPH2 was phosphorylated at Ser19, a phosphorylation site not present in TPH1 [19].
  • In humans, two different TPH genes exist, located on chromosomes 11 and 12, respectively, and encoding two enzymes (TPH1 and TPH2) with an overall sequence identity of 71% [19].
  • METHODS: DNA from the Taiwanese Han and Bunun was subjected to sequence for screening genetic variation in the coding and promoter regions of the TPH1 locus [20].
  • RESULTS: Three variants in the TPH1 promoter region were identified, and the markers are in complete linkage disequilibrium in both populations [20].

Anatomical context of TPH1


Associations of TPH1 with chemical compounds

  • TPH2 is more soluble than TPH1, has a higher molecular weight and different kinetic properties, including a lower catalytic efficiency towards phenylalanine than TPH1 [19].
  • Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied [25].
  • Two isoforms (TPH1 and TPH2) having tryptophan hydroxylating activity were identified [26].
  • The positive heterosis effects with respect to nicotine addiction and personality support the idea that the TPH1 gene exerts pleiotropic effects [27].
  • Tyrosine-, tryptophan- and phenylalanine hydroxylase (TH, TPH and PAH, respectively) were transiently activated at low urea concentrations and rapidly inactivated in >3 M urea [28].

Other interactions of TPH1

  • Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders [29].
  • HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction [30].
  • Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH [31].
  • In vitro binding showed that TPH does not bind to exon 1 of huntingtin in a polyglutamine-dependent manner [9].
  • The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined [32].

Analytical, diagnostic and therapeutic context of TPH1

  • These antibodies allow the differentiation of TPH1 and TPH2 upon immunoblotting, immunoprecipitation, and immunocytochemical staining of tissue sections from brain and gut [1].
  • The presymptomatic inhibition of TPH activity in the R6/2 mice may help explain the functional consequences of HD and provide insights into new targets for pharmacotherapy [9].
  • Because the antibody does not cross react with tyrosine hydroxylase as defined in Western blotting or brain sections, these positive structures may contain TPH [33].
  • By examining introns of the human TPH gene by PCR amplification and analysis by the single-strand conformational polymorphism (SSCP) technique, an SSCP was revealed with two alleles that occur with frequencies of .40 and .60 in unrelated Caucasians [34].
  • Four TPH mRNA species were detected by Northern blot with pineal gland and carcinoid tumor RNAs [35].


  1. Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies. Sakowski, S.A., Geddes, T.J., Thomas, D.M., Levi, E., Hatfield, J.S., Kuhn, D.M. Brain Res. (2006) [Pubmed]
  2. Development of antithrombotic miniribozymes that target peripheral tryptophan hydroxylase. Peter, J.U., Alenina, N., Bader, M., Walther, D.J. Mol. Cell. Biochem. (2007) [Pubmed]
  3. Gene expression in midgut carcinoid tumors: potential targets for immunotherapy. Vikman, S., Essand, M., Cunningham, J.L., de la Torre, M., Oberg, K., Tötterman, T.H., Giandomenico, V. Acta oncologica (Stockholm, Sweden) (2005) [Pubmed]
  4. Identification of the site of interaction of the 14-3-3 protein with phosphorylated tryptophan hydroxylase. Ichimura, T., Uchiyama, J., Kunihiro, O., Ito, M., Horigome, T., Omata, S., Shinkai, F., Kaji, H., Isobe, T. J. Biol. Chem. (1995) [Pubmed]
  5. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. Söderbergh, A., Myhre, A.G., Ekwall, O., Gebre-Medhin, G., Hedstrand, H., Landgren, E., Miettinen, A., Eskelin, P., Halonen, M., Tuomi, T., Gustafsson, J., Husebye, E.S., Perheentupa, J., Gylling, M., Manns, M.P., Rorsman, F., Kämpe, O., Nilsson, T. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  6. Postmortem parietal cortex TPH2 expression is not altered in schizophrenic, unipolar-depressed, and bipolar patients vs control subjects. Shamir, A., Shaltiel, G., Levi, I., Belmaker, R.H., Agam, G. J. Mol. Neurosci. (2005) [Pubmed]
  7. Monoamine oxidase a and tryptophan hydroxylase gene polymorphisms: are they associated with bipolar disorder? Preisig, M., Ferrero, F., Malafosse, A. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice. (2005) [Pubmed]
  8. Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes. Pooley, E.C., Houston, K., Hawton, K., Harrison, P.J. Psychological medicine. (2003) [Pubmed]
  9. Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease. Yohrling IV, G.J., Jiang, G.C., DeJohn, M.M., Robertson, D.J., Vrana, K.E., Cha, J.H. J. Neurochem. (2002) [Pubmed]
  10. Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression. Anttila, S., Huuhka, K., Huuhka, M., Rontu, R., Mattila, K.M., Leinonen, E., Lehtimäki, T. Journal of neural transmission (Vienna, Austria : 1996) (2007) [Pubmed]
  11. Molecular structure of a double helical DNA fragment intercalator complex between deoxy CpG and a terpyridine platinum compound. Wang, A.H., Nathans, J., van der Marel, G., van Boom, J.H., Rich, A. Nature (1978) [Pubmed]
  12. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Nielsen, D.A., Virkkunen, M., Lappalainen, J., Eggert, M., Brown, G.L., Long, J.C., Goldman, D., Linnoila, M. Arch. Gen. Psychiatry (1998) [Pubmed]
  13. Association between the tryptophan hydroxylase gene and manic-depressive illness. Bellivier, F., Leboyer, M., Courtet, P., Buresi, C., Beaufils, B., Samolyk, D., Allilaire, J.F., Feingold, J., Mallet, J., Malafosse, A. Arch. Gen. Psychiatry (1998) [Pubmed]
  14. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Nielsen, D.A., Goldman, D., Virkkunen, M., Tokola, R., Rawlings, R., Linnoila, M. Arch. Gen. Psychiatry (1994) [Pubmed]
  15. Interaction between the tryptophan hydroxylase gene and the serotonin transporter gene in schizophrenia but not in bipolar or unipolar affective disorders. Chotai, J., Serretti, A., Lorenzi, C. Neuropsychobiology (2005) [Pubmed]
  16. Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells. Slominski, A., Semak, I., Pisarchik, A., Sweatman, T., Szczesniewski, A., Wortsman, J. FEBS Lett. (2002) [Pubmed]
  17. Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders. Serretti, A., Lilli, R., Lorenzi, C., Gasperini, M., Smeraldi, E. Journal of psychiatric research. (1999) [Pubmed]
  18. Investigation of serotonin-related genes in antidepressant response. Peters, E.J., Slager, S.L., McGrath, P.J., Knowles, J.A., Hamilton, S.P. Mol. Psychiatry (2004) [Pubmed]
  19. Different properties of the central and peripheral forms of human tryptophan hydroxylase. McKinney, J., Knappskog, P.M., Haavik, J. J. Neurochem. (2005) [Pubmed]
  20. A functional polymorphism in the promoter region of the tryptophan hydroxylase gene is associated with alcohol dependence in one aboriginal group in Taiwan. Sun, H.S., Fann, C.S., Lane, H.Y., Chang, Y.T., Chang, C.J., Liu, Y.L., Cheng, A.T. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  21. Functional Domains of Human Tryptophan Hydroxylase 2 (hTPH2). Carkaci-Salli, N., Flanagan, J.M., Martz, M.K., Salli, U., Walther, D.J., Bader, M., Vrana, K.E. J. Biol. Chem. (2006) [Pubmed]
  22. A unique central tryptophan hydroxylase isoform. Walther, D.J., Bader, M. Biochem. Pharmacol. (2003) [Pubmed]
  23. Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: A post-mortem study. Zill, P., B??ttner, A., Eisenmenger, W., M??ller, H.J., Ackenheil, M., Bondy, B. Journal of psychiatric research (2007) [Pubmed]
  24. FLUOXETINE modifies the expression of serotonergic markers in a differentiation-dependent fashion in the mesencephalic neural cell line A1 mes c-myc. Di Lieto, A., Leo, D., Volpicelli, F., di Porzio, U., Colucci-D'Amato, L. Brain Res. (2007) [Pubmed]
  25. Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women. Sun, H.S., Tsai, H.W., Ko, H.C., Chang, F.M., Yeh, T.L. Genes Brain Behav. (2004) [Pubmed]
  26. Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels. Nakamura, K., Sugawara, Y., Sawabe, K., Ohashi, A., Tsurui, H., Xiu, Y., Ohtsuji, M., Lin, Q.S., Nishimura, H., Hasegawa, H., Hirose, S. J. Neurosci. (2006) [Pubmed]
  27. Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality. Reuter, M., Hennig, J. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  28. Different stabilities and denaturation pathways for structurally related aromatic amino acid hydroxylases. Kleppe, R., Haavik, J. FEBS Lett. (2004) [Pubmed]
  29. Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders. Serretti, A., Cristina, S., Lilli, R., Cusin, C., Lattuada, E., Lorenzi, C., Corradi, B., Grieco, G., Costa, A., Santorelli, F., Barale, F., Nappi, G., Smeraldi, E. Am. J. Med. Genet. (2002) [Pubmed]
  30. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Eley, T.C., Sugden, K., Corsico, A., Gregory, A.M., Sham, P., McGuffin, P., Plomin, R., Craig, I.W. Mol. Psychiatry (2004) [Pubmed]
  31. A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Martínez, A., Knappskog, P.M., Haavik, J. Current medicinal chemistry. (2001) [Pubmed]
  32. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Rotondo, A., Mazzanti, C., Dell'Osso, L., Rucci, P., Sullivan, P., Bouanani, S., Gonnelli, C., Goldman, D., Cassano, G.B. The American journal of psychiatry. (2002) [Pubmed]
  33. Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts. Yu, P.L., Fujimura, M., Okumiya, K., Kinoshita, M., Hasegawa, H., Fujimiya, M. J. Comp. Neurol. (1999) [Pubmed]
  34. Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Nielsen, D.A., Dean, M., Goldman, D. Am. J. Hum. Genet. (1992) [Pubmed]
  35. The human tryptophan hydroxylase gene. An unusual splicing complexity in the 5'-untranslated region. Boularand, S., Darmon, M.C., Mallet, J. J. Biol. Chem. (1995) [Pubmed]
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