Part:BBa_K5378001

Trp hydroxylase-1 (TPH1)

Trp hydroxylase-1 (TPH1) are rate-limiting enzymes in Trp metabolism. Sequence and Features

Assembly Compatibility:

• 10
  COMPATIBLE WITH RFC[10]
• 12
  COMPATIBLE WITH RFC[12]
• 21
  COMPATIBLE WITH RFC[21]
• 23
  COMPATIBLE WITH RFC[23]
• 25
  COMPATIBLE WITH RFC[25]
• 1000
  COMPATIBLE WITH RFC[1000]

Usage and Biology

A small amount of Trp is catalyzed to 5-HTP by TPH (Figure).Aromatic L-amino acid decarboxylase interacts with the cofactor pyridoxal-5’-phosphate to convert 5-HTP to 5-HT. 5-HT is a monoamine neurotransmitter in the human central nervous sys tem and is also known as serotonin because it can cause vascular smooth muscle contraction when present in the blood. The synthesis of 5-HT takes place in both the gut and brain.Peripheral 5-HT is primarily synthesized by TPH1 in the enterochromaffin cells. 5-HT is subsequently stored in platelets and contributes to various physiological functions, including the regulation of vasocontraction and proliferation of vascular smooth muscle cells.

We learned that 5-HT can be further converted to melatonin, which further regulates the sleep-wake cycle by consulting the literature.Furthermore, 5-HT in the gut has been reported to be involved in the production of melatonin.

After being metabolized by gut bacteria, aromatic amino acids from food can produce monoamine false neurotransmitters, such as phenylalanine being metabolized into phenylethylamine, and tyrosine into tyramine. Tryptophan, through different metabolic pathways, can be converted into kynurenine, serotonin, and indole.

Patients who develop liver failure can not digest those aromatic amino acids properly, and this can lead to false neuro-transmitters accumulation, causing neuro system symptoms.

Functional Verification

We designed a plasmid that can be transformed into EcN to express tryptophan hydroxylase 1 (TPH1), enabling the conversion of tryptophan (Trp) into serotonin (5-HT) and reducing excess aromatic amino acids. Since serotonin synthesized in the gut cannot cross the blood-brain barrier (BBB) or affect central nervous system function, there is no concern about adverse effects on the central nervous system.

Reference

[1]Daubert, E.A., and Condron, B.G. (2010). Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci. 33, 424–434. https://doi.org/10.1016/j.tins.2010.05.005.

[2] Watts, S.W., Morrison, S.F., Davis, R.P., and Barman, S.M. (2012). Sero tonin and blood pressure regulation. Pharmacol. Rev. 64, 359–388. https://doi.org/10.1124/pr.111.004697.

[3]Chen,C.Q., Fichna, J., Bashashati, M., Li, Y.Y., and Storr, M. (2011). Dis tribution, function and physiological role of melatonin in the lower gut. World J. Gastroenterol. 17, 3888–3898. https://doi.org/10.3748/wjg. v17.i34.3888.

[4]Xue C, Li G, Zheng Q, Gu X, Shi Q, Su Y, Chu Q, Yuan X, Bao Z, Lu J, Li L. Tryptophan metabolism in health and disease. Cell Metab. 2023 Aug 8;35(8):1304-1326. doi: 10.1016/j.cmet.2023.06.004. Epub 2023 Jun 22. PMID: 37352864.