View source for Tryptophan hydroxylase

{{Short description|Class of enzymes}}
{{stack begin}}
{{infobox enzyme
| Name       = tryptophan 5-monooxygenase
| EC_number  = 1.14.16.4
| CAS_number = 9037-21-2
| GO_code    = 0004510
| image      = 1mlw.jpg
| width      = 270
| caption    = tryptophan 5-monooxygenase monomer, Human
}}
{{protein
| Name = [[TPH1|tryptophan hydroxylase 1 (tryptophan 5-monooxygenase)]]
| caption = 
| image = 
| width = 
| HGNCid = 12008
| Symbol = [[TPH1]]
| AltSymbols = TPRH, TPH
| EntrezGene = 7166
| OMIM = 191060
| RefSeq = NM_004179
| UniProt = P17752
| PDB = 1MLW
| ECnumber = 1.14.16.4
| Chromosome = 11
| Arm = p
| Band = 15.3
| LocusSupplementaryData = -p14
}}
{{protein
| Name = [[TPH2|tryptophan hydroxylase 2]]
| caption = 
| image = 
| width = 
| HGNCid = 20692
| Symbol = [[TPH2]]
| AltSymbols = 
| EntrezGene = 121278
| OMIM = 607478
| RefSeq = NM_173353
| UniProt = Q8IWU9
| PDB = 
| ECnumber = 
| Chromosome = 12
| Arm = q
| Band = 15
| LocusSupplementaryData = 
}}
{{stack end}}

'''Tryptophan hydroxylase''' ('''TPH''') is an [[enzyme]] ({{EC number|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 hydroxylase]]s. TPH catalyzes the following chemical reaction

: L-[[tryptophan]] + [[tetrahydrobiopterin]] + O<sub>2</sub> <math>\rightleftharpoons</math> [[5-Hydroxytryptophan]] + [[dihydrobiopterin]] + H<sub>2</sub>O

It employs one additional [[cofactor (biochemistry)|cofactor]], [[iron]].

== Function ==
<!--
{{stack|
{{Enzymatic Reaction
|foward_enzyme=Tryptophan hydroxylase
|reverse_enzyme=
|substrate=[[Tryptophan]]
|product=[[5-HTP]]
|reaction_direction_(forward/reversible/reverse)=forward
|minor_foward_substrate(s)=O<sub>2</sub><br />[[Tetrahydrobiopterin|BH<sub>4</sub>]]
|minor_foward_product(s)=H<sub>2</sub>O<br />BH<sub>2</sub>
|minor_reverse_substrate(s)=
|minor_reverse_product(s)=
|substrate_image=Tryptophan_simple.png
|substrate_image_size=120px
|product_image=5-hydroxytryptophan.png
|product_image_size=120px
}}
}}
-->
It 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 hydroxylase]]s, catalyzing key steps in important metabolic pathways.<ref name="pmid11747434">{{cite journal | vauthors = McKinney J, Teigen K, Frøystein NA, Salaün C, Knappskog PM, Haavik J, Martínez A | title = Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity | journal = Biochemistry | volume = 40 | issue = 51 | pages = 15591–601 | date = December 2001 | pmid = 11747434 | doi = 10.1021/bi015722x | url = http://www.bh4.org/pdf/mckinney.pdf | url-status = dead | archive-url = https://web.archive.org/web/20081217045622/http://www.bh4.org/pdf/mckinney.pdf | archive-date = 2008-12-17 }}</ref> Analogously to [[phenylalanine hydroxylase]] and [[tyrosine hydroxylase]], this enzyme uses (6R)-L-erythro-5,6,7,8-[[tetrahydrobiopterin]] (BH<sub>4</sub>) and dioxygen as cofactors.<ref name="urlBH4 Databases">{{cite web| url =http://www.bh4.org/BH4_Deficiency_Biochemistry.asp| title =tetrahydrobiopterin| year =2005| work =BH4 Databases| publisher =BH4.org| archive-url =https://web.archive.org/web/20061206195735/http://bh4.org/BH4_Deficiency_Biochemistry.asp| archive-date =2006-12-06| url-status =dead}}</ref>

In humans, the stimulation of serotonin production by administration of tryptophan has an antidepressant effect<ref>{{cite journal | vauthors = Lindseth G, Helland B, Caspers J | title = The effects of dietary tryptophan on affective disorders | journal = Archives of Psychiatric Nursing | volume = 29 | issue = 2 | pages = 102–7 | date = April 2015 | pmid = 25858202 | pmc = 4393508 | doi = 10.1016/j.apnu.2014.11.008 }}</ref><ref>{{cite journal | vauthors = Coppen A, Shaw DM, Herzberg B, Maggs R | title = Tryptophan in the treatment of depression | journal = Lancet | volume = 2 | issue = 7527 | pages = 1178–80 | date = December 1967 | pmid = 4168381 | doi = 10.1016/s0140-6736(67)91894-6 | series = Originally published as Volume 2, Issue 7527 }}</ref> and inhibition of tryptophan hydroxylase (e.g. by [[p-Chlorophenylalanine]]) may precipitate depression.<ref name="pmid12379098">{{cite journal | vauthors = Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC | title = Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin | journal = Biochemistry | volume = 41 | issue = 42 | pages = 12569–74 | date = October 2002 | pmid = 12379098 | doi = 10.1021/bi026561f }}</ref>

The [[Enzyme activity|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 ==
In 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%).<ref name="pmid14563478">{{cite journal | vauthors = Walther DJ, Bader M | title = A unique central tryptophan hydroxylase isoform | journal = Biochemical Pharmacology | volume = 66 | issue = 9 | pages = 1673–80 | date = November 2003 | pmid = 14563478 | doi = 10.1016/S0006-2952(03)00556-2 }}</ref>

* TPH1 is mostly expressed in tissues that express serotonin (a neurotransmitter) in the periphery ([[skin]], [[Gut (zoology)|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 ==
Tryptophan hydroxylase inhibitors include [[fenclonine]] (''para''-chlorophenylalanine or PCPA) and [[telotristat ethyl]] (a [[prodrug]] of [[telotristat]]).<ref name="WaløenKleppeMartinez2017">{{cite journal | vauthors = Waløen K, Kleppe R, Martinez A, Haavik J | title = Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease | journal = Expert Opin Ther Targets | volume = 21 | issue = 2 | pages = 167–180 | date = February 2017 | pmid = 27973928 | doi = 10.1080/14728222.2017.1272581 | url = | hdl = 1956/17486 | hdl-access = free }}</ref><ref name="Bader2020">{{cite journal | vauthors = Bader M | title = Inhibition of serotonin synthesis: A novel therapeutic paradigm | journal = Pharmacol Ther | volume = 205 | issue = | pages = 107423 | date = January 2020 | pmid = 31629717 | doi = 10.1016/j.pharmthera.2019.107423 | url = }}</ref>

== Additional images ==
<gallery>
 Image:5htsynt 2.png |The pathway for the synthesis of serotonin from tryptophan
 Image:Trp-5ht-pathway.svg |Metabolic pathway from tryptophan to serotonin
</gallery>

== See also ==
* {{Portal-inline|Biology}}

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Friedman PA, Kappelman AH, Kaufman S | title = Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain | journal = The Journal of Biological Chemistry | volume = 247 | issue = 13 | pages = 4165–73 | date = July 1972 | doi = 10.1016/S0021-9258(19)45055-2 | pmid = 4402511 | doi-access = free }}
* {{cite journal | vauthors = Hamon M, Bourgoin S, Artaud F, Glowinski J | title = 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 = Journal of Neurochemistry | volume = 33 | issue = 5 | pages = 1031–42 | date = November 1979 | pmid = 315449 | doi = 10.1111/j.1471-4159.1979.tb05239.x | s2cid = 12415965 }}
* {{cite journal | vauthors = Ichiyama A, Nakamura S, Nishizuka Y, Hayaishi O | title = Enzymic studies on the biosynthesis of serotonin in mammalian brain | journal = The Journal of Biological Chemistry | volume = 245 | issue = 7 | pages = 1699–709 | date = April 1970 | doi = 10.1016/S0021-9258(19)77149-X | pmid = 5309585 | doi-access = free }}
* {{cite journal | vauthors = Jequier E, Robinson DS, Lovenberg W, Sjoerdsma A | title = Further studies on tryptophan hydroxylase in rat brainstem and beef pineal | journal = Biochemical Pharmacology | volume = 18 | issue = 5 | pages = 1071–81 | date = May 1969 | pmid = 5789774 | doi = 10.1016/0006-2952(69)90111-7 }}
* {{cite journal | vauthors = Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC | title = Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin | journal = Biochemistry | volume = 41 | issue = 42 | pages = 12569–74 | date = October 2002 | pmid = 12379098 | doi = 10.1021/bi026561f }}
* {{cite journal | vauthors = Windahl MS, Petersen CR, Christensen HE, Harris P | title = Crystal structure of tryptophan hydroxylase with bound amino acid substrate | journal = Biochemistry | volume = 47 | issue = 46 | pages = 12087–94 | date = November 2008 | pmid = 18937498 | doi = 10.1021/bi8015263 }}
{{refend}}

== External links ==
*{{MeshName|Tryptophan+Hydroxylase}}
* See also [http://www.proteopedia.org/wiki/index.php/Tryptophan_hydroxylase tryptophan hydroxylase] in [http://www.proteopedia.org Proteopedia]

{{Neurotransmitter metabolism enzymes}}
{{Dioxygenases}}
{{Enzymes}}
{{Monoamine metabolism modulators}}

[[Category:EC 1.14.16]]


{{1.14-enzyme-stub}}