Biology:TPH1
Generic protein structure example |
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.[1][citation needed]
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)
References
- ↑ 1.0 1.1 "Entrez Gene: TPH1 tryptophan hydroxylase 1 (tryptophan 5-monooxygenase)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7166.
- ↑ "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. doi:10.1089/jir.1988.8.705. PMID 3148005.
- ↑ 3.0 3.1 "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science 299 (5603): 76. January 2003. doi:10.1126/science.1078197. PMID 12511643.
- ↑ "Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study". Am. J. Med. Genet. 81 (1): 13–7. 1998. doi:10.1002/(SICI)1096-8628(19980207)81:1<13::AID-AJMG3>3.0.CO;2-O. PMID 9514581.
- ↑ "No association between tryptophan hydroxylase gene polymorphism and Alzheimer's disease". Neuropsychobiology 43 (1): 1–4. January 2001. doi:10.1159/000054856. PMID 11150890.
- ↑ "Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database". Nat. Genet. 40 (7): 827–34. July 2008. doi:10.1038/ng.171. PMID 18583979.
Further reading
- "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. doi:10.1007/s00439-005-0113-x. PMID 16450114.
- "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. PMID 1463016.
- "Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3----p14 by in situ hybridization.". Cytogenet. Cell Genet. 56 (3–4): 157–9. 1991. doi:10.1159/000133075. PMID 2055111.
- "Complete coding sequence of human tryptophan hydroxylase.". Nucleic Acids Res. 18 (14): 4257. 1990. doi:10.1093/nar/18.14.4257. PMID 2377472.
- "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. doi:10.1007/BF01534499. PMID 2889273.
- "Identification of the site of interaction of the 14-3-3 protein with phosphorylated tryptophan hydroxylase.". J. Biol. Chem. 270 (48): 28515–8. 1996. doi:10.1074/jbc.270.48.28515. PMID 7499362.
- "Cloning and expression of rabbit and human brain tryptophan hydroxylase cDNA in Escherichia coli.". Arch. Biochem. Biophys. 315 (2): 445–53. 1995. doi:10.1006/abbi.1994.1523. PMID 7986090. https://zenodo.org/record/1229394.
- "Demonstration of the phosphorylation-dependent interaction of tryptophan hydroxylase with the 14-3-3 protein.". Biochem. Biophys. Res. Commun. 194 (1): 144–9. 1993. doi:10.1006/bbrc.1993.1796. PMID 8101440.
- "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. doi:10.1046/j.1471-4159.1997.68052220.x. PMID 9109552.
- "Alternative splicing at the 3'-cDNA of human tryptophan hydroxylase.". J. Neurochem. 71 (4): 1769–72. 1998. doi:10.1046/j.1471-4159.1998.71041769.x. PMID 9751214.
- "Regional distribution and cellular expression of tryptophan hydroxylase messenger RNA in postmortem human brainstem and pineal gland.". J. Neurochem. 72 (5): 2065–73. 1999. doi:10.1046/j.1471-4159.1999.0722065.x. PMID 10217286.
- "Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts.". J. Comp. Neurol. 411 (4): 654–65. 1999. doi:10.1002/(SICI)1096-9861(19990906)411:4<654::AID-CNE9>3.0.CO;2-H. PMID 10421874.
- "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. doi:10.1016/S0167-4838(99)00184-3. PMID 10525150. https://zenodo.org/record/1259897.
- "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. doi:10.1021/bi015722x. PMID 11747434.
- "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. doi:10.1002/ajmg.10356. PMID 11992558.
- "Serotoninergic and melatoninergic systems are fully expressed in human skin.". FASEB J. 16 (8): 896–8. 2002. doi:10.1096/fj.01-0952fje. PMID 12039872.
- "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. doi:10.1046/j.1471-4159.2002.01084.x. PMID 12354289.
- "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. doi:10.1021/bi026561f. PMID 12379098.
- "Serotoninergic system in hamster skin.". J. Invest. Dermatol. 119 (4): 934–42. 2002. doi:10.1046/j.1523-1747.2002.00156.x. PMID 12406341.
- "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. doi:10.1038/sj.mp.4001150. PMID 12476329.
- "Crystal structure of tryptophan hydroxylase with bound amino acid substrate.". Biochemistry 47 (46): 12087–94. 2008. doi:10.1021/bi8015263. PMID 18937498.
External links
- Overview of all the structural information available in the PDB for UniProt: P17752 (Tryptophan 5-hydroxylase 1) at the PDBe-KB.
Original source: https://en.wikipedia.org/wiki/TPH1.
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