Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction
| tryptophan 5-monooxygenase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 tryptophan 5-monooxygenase monomer, Human | |||||||||
| Identifiers | |||||||||
| EC no. | 1.14.16.4 | ||||||||
| CAS no. | 9037-21-2 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
| tryptophan hydroxylase 1 (tryptophan 5-monooxygenase) | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | TPH1 | ||||||
| Alt. symbols | TPRH, TPH | ||||||
| NCBI gene | 7166 | ||||||
| HGNC | 12008 | ||||||
| OMIM | 191060 | ||||||
| PDB | 1MLW | ||||||
| RefSeq | NM_004179 | ||||||
| UniProt | P17752 | ||||||
| Other data | |||||||
| EC number | 1.14.16.4 | ||||||
| Locus | Chr. 11 p15.3-p14 | ||||||
| |||||||
| tryptophan hydroxylase 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | TPH2 | ||||||
| NCBI gene | 121278 | ||||||
| HGNC | 20692 | ||||||
| OMIM | 607478 | ||||||
| RefSeq | NM_173353 | ||||||
| UniProt | Q8IWU9 | ||||||
| Other data | |||||||
| Locus | Chr. 12 q15 | ||||||
| |||||||
- L-tryptophan + tetrahydrobiopterin + O2 5-Hydroxytryptophan + dihydrobiopterin + H2O
Function
editIt is responsible for addition of the -OH group (hydroxylation) to the 5 position to form the amino acid 5-hydroxytryptophan (5-HTP), which is the initial and rate-limiting step in the synthesis of the neurotransmitter serotonin. It is also the first enzyme in the synthesis of melatonin.
Tryptophan hydroxylase (TPH), tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH) are members of a superfamily of aromatic amino acid hydroxylases, catalyzing key steps in important metabolic pathways.[1] Analogously to phenylalanine hydroxylase and tyrosine hydroxylase, this enzyme uses (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and dioxygen as cofactors.[2]
In humans, the stimulation of serotonin production by administration of tryptophan has an antidepressant effect[3][4] and inhibition of tryptophan hydroxylase (e.g. by p-Chlorophenylalanine) may precipitate depression.[5]
The activity of tryptophan hydroxylase (i.e. the rate at which it converts L-tryptophan into the serotonin precursor L-5-hydroxytryptophan) can be increased when it undergoes phosphorylation. Protein Kinase A, for example, can phosphorylate tryptophan hydroxylase, thus increasing its activity.
Isoforms
editIn humans, as well as in other mammals, there are two distinct TPH genes. In humans, these genes are located on chromosomes 11 and 12 and encode two different homologous enzymes TPH1 and TPH2 (sequence identity 71%).[6]
- TPH1 is mostly expressed in tissues that express serotonin (a neurotransmitter) in the periphery (skin, gut, pineal gland) but it is also expressed in the central nervous system.
- On the other hand, TPH2 is exclusively expressed in neuronal cell types and is the predominant isoform in the central nervous system.
Inhibitors
editTryptophan hydroxylase inhibitors include fenclonine (para-chlorophenylalanine or PCPA) and telotristat ethyl (a prodrug of telotristat).[7][8]
Additional images
edit-
The pathway for the synthesis of serotonin from tryptophan -
Metabolic pathway from tryptophan to serotonin
See also
edit
References
edit- ^ McKinney J, Teigen K, Frøystein NA, Salaün C, Knappskog PM, Haavik J, Martínez A (December 2001). "Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity" (PDF). Biochemistry. 40 (51): 15591–601. doi:10.1021/bi015722x. PMID 11747434. Archived from the original (PDF) on 2008-12-17.
- ^ "tetrahydrobiopterin". BH4 Databases. BH4.org. 2005. Archived from the original on 2006-12-06.
- ^ Lindseth G, Helland B, Caspers J (April 2015). "The effects of dietary tryptophan on affective disorders". Archives of Psychiatric Nursing. 29 (2): 102–7. doi:10.1016/j.apnu.2014.11.008. PMC 4393508. PMID 25858202.
- ^ Coppen A, Shaw DM, Herzberg B, Maggs R (December 1967). "Tryptophan in the treatment of depression". Lancet. Originally published as Volume 2, Issue 7527. 2 (7527): 1178–80. doi:10.1016/s0140-6736(67)91894-6. PMID 4168381.
- ^ Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC (October 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. PMID 12379098.
- ^ Walther DJ, Bader M (November 2003). "A unique central tryptophan hydroxylase isoform". Biochemical Pharmacology. 66 (9): 1673–80. doi:10.1016/S0006-2952(03)00556-2. PMID 14563478.
- ^ Waløen K, Kleppe R, Martinez A, Haavik J (February 2017). "Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease". Expert Opin Ther Targets. 21 (2): 167–180. doi:10.1080/14728222.2017.1272581. hdl:1956/17486. PMID 27973928.
- ^ Bader M (January 2020). "Inhibition of serotonin synthesis: A novel therapeutic paradigm". Pharmacol Ther. 205: 107423. doi:10.1016/j.pharmthera.2019.107423. PMID 31629717.
Further reading
edit- Friedman PA, Kappelman AH, Kaufman S (July 1972). "Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain". The Journal of Biological Chemistry. 247 (13): 4165–73. doi:10.1016/S0021-9258(19)45055-2. PMID 4402511.
- Hamon M, Bourgoin S, Artaud F, Glowinski J (November 1979). "The role of intraneuronal 5-HT and of tryptophan hydroxylase activation in the control of 5-HT synthesis in rat brain slices incubated in K+-enriched medium". Journal of Neurochemistry. 33 (5): 1031–42. doi:10.1111/j.1471-4159.1979.tb05239.x. PMID 315449. S2CID 12415965.
- Ichiyama A, Nakamura S, Nishizuka Y, Hayaishi O (April 1970). "Enzymic studies on the biosynthesis of serotonin in mammalian brain". The Journal of Biological Chemistry. 245 (7): 1699–709. doi:10.1016/S0021-9258(19)77149-X. PMID 5309585.
- Jequier E, Robinson DS, Lovenberg W, Sjoerdsma A (May 1969). "Further studies on tryptophan hydroxylase in rat brainstem and beef pineal". Biochemical Pharmacology. 18 (5): 1071–81. doi:10.1016/0006-2952(69)90111-7. PMID 5789774.
- Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC (October 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. PMID 12379098.
- Windahl MS, Petersen CR, Christensen HE, Harris P (November 2008). "Crystal structure of tryptophan hydroxylase with bound amino acid substrate". Biochemistry. 47 (46): 12087–94. doi:10.1021/bi8015263. PMID 18937498.
External links
edit- Tryptophan+Hydroxylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- See also tryptophan hydroxylase in Proteopedia