Tryptophan hydroxylase explained

tryptophan 5-monooxygenase
Ec Number:	1.14.16.4
Cas Number:	9037-21-2
Go Code:	0004510
Width:	270

Tryptophan hydroxylase (TPH) is an enzyme 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

L-tryptophan + tetrahydrobiopterin + O₂

\rightleftharpoons 5-Hydroxytryptophan + dihydrobiopterin + H₂O

It employs one additional cofactor, iron.

Function

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 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

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%).^[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.

Further reading

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

External links

• • See also tryptophan hydroxylase in Proteopedia

Notes and References

1. McKinney J, Teigen K, Frøystein NA, Salaün C, Knappskog PM, Haavik J, Martínez A . Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity . Biochemistry . 40 . 51 . 15591–601 . December 2001 . 11747434 . 10.1021/bi015722x . dead . https://web.archive.org/web/20081217045622/http://www.bh4.org/pdf/mckinney.pdf . 2008-12-17 .
2. Web site: tetrahydrobiopterin. 2005. BH4 Databases. BH4.org. https://web.archive.org/web/20061206195735/http://bh4.org/BH4_Deficiency_Biochemistry.asp. 2006-12-06. dead.
3. Lindseth G, Helland B, Caspers J . The effects of dietary tryptophan on affective disorders . Archives of Psychiatric Nursing . 29 . 2 . 102–7 . April 2015 . 25858202 . 4393508 . 10.1016/j.apnu.2014.11.008 .
4. Coppen A, Shaw DM, Herzberg B, Maggs R . Tryptophan in the treatment of depression . Lancet . 2 . 7527 . 1178–80 . December 1967 . 4168381 . 10.1016/s0140-6736(67)91894-6 . Originally published as Volume 2, Issue 7527 .
5. Wang L, Erlandsen H, Haavik J, Knappskog PM, Stevens RC . Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin . Biochemistry . 41 . 42 . 12569–74 . October 2002 . 12379098 . 10.1021/bi026561f .
6. Walther DJ, Bader M . A unique central tryptophan hydroxylase isoform . Biochemical Pharmacology . 66 . 9 . 1673–80 . November 2003 . 14563478 . 10.1016/S0006-2952(03)00556-2 .