It is responsible for addition of the -OH group (hydroxylation) to the 5 position to form theamino acid5-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.
In humans, the stimulation of serotonin production by administration of tryptophan has an antidepressant effect[3][4] and inhibition of tryptophan hydroxylase (e.g. byp-chlorophenylalanine) may precipitate depression.[5]
Theactivity of tryptophan hydroxylase (i.e., the rate at which it convertsL-tryptophan into the serotonin precursorL-5-hydroxytryptophan) can be increased when it undergoesphosphorylation.Protein Kinase A, for example, can phosphorylate tryptophan hydroxylase, thus increasing its activity.
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 enzymesTPH1 andTPH2 (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 inneuronal cell types and is the predominant isoform in thecentral nervous system.
^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.PMID4168381.
^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.PMID12379098.
^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.PMID27973928.
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.PMID315449.S2CID12415965.
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.PMID5789774.
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.PMID12379098.
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.PMID18937498.
