Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1gene.[5]
TPH1 was first discovered to synthesize serotonin in 1988[6] and was thought that there only was a single TPH gene until 2003, while a second form was found in the mouse (Tph2), rat and human brain (TPH2) and the original TPH was then renamed to TPH1.[7]
Tryptophan hydroxylases catalyze the biopterin-dependent monooxygenation of tryptophan to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to form the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). It is the rate-limiting enzyme in the biosynthesis of serotonin.
Tryptophan hydroxylase is important for synthesizing indoleamine neurotransmitters and related compounds in the body and brain, including serotonin, melatonin, tryptamine, N-methyltryptamine, and N,N-dimethyltryptamine. TPH1 is expressed in the body, but not the brain.[7]
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,[8] while a case-control study (2001) could find no association between polymorphisms and Alzheimer's disease.[9]
One human mutant of TPH1, A218C found in intron 7, is highly associated with schizophrenia.[10] 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.
^Finocchiaro LM, Arzt ES, Fernández-Castelo S, Criscuolo M, Finkielman S, Nahmod VE (December 1988). "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. doi:10.1089/jir.1988.8.705. PMID3148005.
^ Jump up to: abWalther 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. PMID12511643. S2CID7095712.
^New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, Mitropoulou V, Siever LJ (1998). "Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study". Am. J. Med. Genet. 81 (1): 13–7. doi:10.1002/(SICI)1096-8628(19980207)81:1<13::AID-AJMG3>3.0.CO;2-O. PMID9514581.
^Wang YC, Tsai SJ, Liu TY, Liu HC, Hong CJ (January 2001). "No association between tryptophan hydroxylase gene polymorphism and Alzheimer's disease". Neuropsychobiology. 43 (1): 1–4. doi:10.1159/000054856. PMID11150890. S2CID39712696.
^Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L (July 2008). "Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database". Nat. Genet. 40 (7): 827–34. doi:10.1038/ng.171. PMID18583979. S2CID21772210.
Further reading[]
Li D, He L (2007). "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. doi:10.1007/s00439-005-0113-x. PMID16450114. S2CID28869541.
Craig SP, Boularand S, Darmon MC, et al. (1991). "Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3----p14 by in situ hybridization". Cytogenet. Cell Genet. 56 (3–4): 157–9. doi:10.1159/000133075. PMID2055111.
Ledley FD, Grenett HE, Bartos DP, et al. (1987). "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. doi:10.1007/BF01534499. PMID2889273. S2CID10999404.
Furukawa Y, Ikuta N, Omata S, et al. (1993). "Demonstration of the phosphorylation-dependent interaction of tryptophan hydroxylase with the 14-3-3 protein". Biochem. Biophys. Res. Commun. 194 (1): 144–9. doi:10.1006/bbrc.1993.1796. PMID8101440.
Austin MC, O'Donnell SM (1999). "Regional distribution and cellular expression of tryptophan hydroxylase messenger RNA in postmortem human brainstem and pineal gland". J. Neurochem. 72 (5): 2065–73. doi:10.1046/j.1471-4159.1999.0722065.x. PMID10217286. S2CID43008.
McKinney J, Teigen K, Frøystein NA, et al. (2002). "Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity". Biochemistry. 40 (51): 15591–601. doi:10.1021/bi015722x. PMID11747434.
Serretti A, Cristina S, Lilli R, et al. (2002). "Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders". Am. J. Med. Genet. 114 (4): 361–9. doi:10.1002/ajmg.10356. PMID11992558.
Slominski A, Pisarchik A, Semak I, et al. (2002). "Serotoninergic and melatoninergic systems are fully expressed in human skin". FASEB J. 16 (8): 896–8. doi:10.1096/fj.01-0952fje. PMID12039872. S2CID17590408.
Wang L, Erlandsen H, Haavik J, et al. (2002). "Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin". Biochemistry. 41 (42): 12569–74. doi:10.1021/bi026561f. PMID12379098.
