TPH1 explained

Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene.^[1]

TPH1 was first discovered to support serotonin synthesis in 1988 by converting tryptophan into 5-hydroxytryptophan.^[2] It was thought that there only was a single TPH gene until 2003. A second form was found in the mouse (Tph2), rat and human brain (TPH2) and the original TPH was then renamed to TPH1.^[3]

Function

Tryptophan hydroxylases catalyze the biopterin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated by aromatic amino acid decarboxylase to form the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). It is the rate-limiting enzyme in the biosynthesis of serotonin.

TPH expression is limited to a few specialized tissues: raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta-cells of the islets of Langerhans, and intestinal and pancreatic enterochromaffin cells.

Clinical significance

Tryptophan hydroxylase is important for synthesizing indoleamine neurotransmitters and related compounds in the body and brain, including serotonin and melatonin. TPH1 is expressed in the body, but not the brain.^[3] Nevertheless, the effect of variations in the TPH1 gene on brain-related variables, such as personality traits and neuropsychiatric disorders, has been studied. For example, one study (1998) found an association between a polymorphism in the gene with impulsive-aggression measures,^[4] while a case-control study (2001) could find no association between polymorphisms and Alzheimer's disease.^[5]

One human mutant of TPH1, A218C found in intron 7, is highly associated with schizophrenia.^[6] Introns are regions of DNA that do not code for the amino acid sequence of a protein and were long considered to be 'junk DNA' lacking purpose. The correlation of an intron mutation with schizophrenia is significant because it suggests that introns have an important role in translation, transcription, or another, possibly unknown, aspect of the production of proteins from DNA.

See also

• Tryptophan hydroxylase
• TPH2
• Rs1799913 (A779C): intron related to figural and numeric creativity
• rs1800532 (A218C)

Further reading

• Li D, He L . Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses. . Hum. Genet. . 119 . 3 . 233–40 . 2007 . 16450114 . 10.1007/s00439-005-0113-x . 28869541 .
• Nielsen DA, Dean M, Goldman D . Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. . Am. J. Hum. Genet. . 51 . 6 . 1366–71 . 1993 . 1463016 . 1682899 .
• Craig SP, Boularand S, Darmon MC, etal . Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3----p14 by in situ hybridization. . Cytogenet. Cell Genet. . 56 . 3–4 . 157–9 . 1991 . 2055111 . 10.1159/000133075 .
• Boularand S, Darmon MC, Ganem Y, etal . Complete coding sequence of human tryptophan hydroxylase. . Nucleic Acids Res. . 18 . 14 . 4257 . 1990 . 2377472 . 10.1093/nar/18.14.4257 . 331198 .
• Ledley FD, Grenett HE, Bartos DP, etal . Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases. . Somat. Cell Mol. Genet. . 13 . 5 . 575–80 . 1987 . 2889273 . 10.1007/BF01534499 . 10999404 .
• Ichimura T, Uchiyama J, Kunihiro O, etal . Identification of the site of interaction of the 14-3-3 protein with phosphorylated tryptophan hydroxylase. . J. Biol. Chem. . 270 . 48 . 28515–8 . 1996 . 7499362 . 10.1074/jbc.270.48.28515 . free .
• Tipper JP, Citron BA, Ribeiro P, Kaufman S . Cloning and expression of rabbit and human brain tryptophan hydroxylase cDNA in Escherichia coli. . Arch. Biochem. Biophys. . 315 . 2 . 445–53 . 1995 . 7986090 . 10.1006/abbi.1994.1523 .
• Furukawa Y, Ikuta N, Omata S, etal . Demonstration of the phosphorylation-dependent interaction of tryptophan hydroxylase with the 14-3-3 protein. . Biochem. Biophys. Res. Commun. . 194 . 1 . 144–9 . 1993 . 8101440 . 10.1006/bbrc.1993.1796 .
• Kuhn DM, Arthur R, States JC . Phosphorylation and activation of brain tryptophan hydroxylase: identification of serine-58 as a substrate site for protein kinase A. . J. Neurochem. . 68 . 5 . 2220–3 . 1997 . 9109552 . 10.1046/j.1471-4159.1997.68052220.x . 24626272 . free .
• Wang GA, Coon SL, Kaufman S . Alternative splicing at the 3'-cDNA of human tryptophan hydroxylase. . J. Neurochem. . 71 . 4 . 1769–72 . 1998 . 9751214 . 10.1046/j.1471-4159.1998.71041769.x . 45630201 . free .
• Austin MC, O'Donnell SM . Regional distribution and cellular expression of tryptophan hydroxylase messenger RNA in postmortem human brainstem and pineal gland. . J. Neurochem. . 72 . 5 . 2065–73 . 1999 . 10217286 . 10.1046/j.1471-4159.1999.0722065.x . 43008 .
• Yu PL, Fujimura M, Okumiya K, etal . Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts. . J. Comp. Neurol. . 411 . 4 . 654–65 . 1999 . 10421874 . 10.1002/(SICI)1096-9861(19990906)411:4<654::AID-CNE9>3.0.CO;2-H . 25930672 .
• Kowlessur D, Kaufman S . Cloning and expression of recombinant human pineal tryptophan hydroxylase in Escherichia coli: purification and characterization of the cloned enzyme. . Biochim. Biophys. Acta . 1434 . 2 . 317–30 . 1999 . 10525150 . 10.1016/S0167-4838(99)00184-3 .
• McKinney J, Teigen K, Frøystein NA, etal . Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity. . Biochemistry . 40 . 51 . 15591–601 . 2002 . 11747434 . 10.1021/bi015722x .
• Serretti A, Cristina S, Lilli R, etal . Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders. . Am. J. Med. Genet. . 114 . 4 . 361–9 . 2002 . 11992558 . 10.1002/ajmg.10356 .
• Slominski A, Pisarchik A, Semak I, etal . Serotoninergic and melatoninergic systems are fully expressed in human skin. . FASEB J. . 16 . 8 . 896–8 . 2002 . 12039872 . 10.1096/fj.01-0952fje . free . 17590408 .
• Yohrling IV GJ, Jiang GC, DeJohn MM, etal . Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease. . J. Neurochem. . 82 . 6 . 1416–23 . 2002 . 12354289 . 10.1046/j.1471-4159.2002.01084.x . 23022076 . free .
• Wang L, Erlandsen H, Haavik J, etal . Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin. . Biochemistry . 41 . 42 . 12569–74 . 2002 . 12379098 . 10.1021/bi026561f .
• Slominski A, Pisarchik A, Semak I, etal . Serotoninergic system in hamster skin. . J. Invest. Dermatol. . 119 . 4 . 934–42 . 2002 . 12406341 . 10.1046/j.1523-1747.2002.00156.x . free .
• Ono H, Shirakawa O, Kitamura N, etal . Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. . Mol. Psychiatry . 7 . 10 . 1127–32 . 2003 . 12476329 . 10.1038/sj.mp.4001150 . free . 20.500.14094/90000364 . free .
• Windahl MS, Petersen CR, ((Christensen HEM)), Harris P . Crystal structure of tryptophan hydroxylase with bound amino acid substrate. . Biochemistry . 47 . 46 . 12087–94 . 2008 . 18937498 . 10.1021/bi8015263 .

Notes and References

1. Web site: Entrez Gene: TPH1 tryptophan hydroxylase 1 (tryptophan 5-monooxygenase).
2. Finocchiaro LM, Arzt ES, Fernández-Castelo S, Criscuolo M, Finkielman S, Nahmod VE . Serotonin and melatonin synthesis in peripheral blood mononuclear cells: stimulation by interferon-gamma as part of an immunomodulatory pathway . J. Interferon Res. . 8 . 6 . 705–16 . December 1988 . 3148005 . 10.1089/jir.1988.8.705.
3. Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M . Synthesis of serotonin by a second tryptophan hydroxylase isoform . Science . 299 . 5603 . 76 . January 2003 . 12511643 . 10.1126/science.1078197 . 7095712 .
4. New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, Mitropoulou V, Siever LJ . Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study . Am. J. Med. Genet. . 81 . 1 . 13–7 . 1998 . 9514581 . 10.1002/(SICI)1096-8628(19980207)81:1<13::AID-AJMG3>3.0.CO;2-O .
5. Wang YC, Tsai SJ, Liu TY, Liu HC, Hong CJ . No association between tryptophan hydroxylase gene polymorphism and Alzheimer's disease . Neuropsychobiology . 43 . 1 . 1–4 . January 2001 . 11150890 . 10.1159/000054856 . 39712696 .
6. Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L . Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database . Nat. Genet. . 40 . 7 . 827–34 . July 2008 . 18583979 . 10.1038/ng.171 . 21772210 .