Tryptophan hydroxylase (TPH) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

() involved in the synthesis of the monoamine neurotransmitter

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

Tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...

phenylalanine hydroxylase Phenylalanine hydroxylase (PAH) () is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a clas ...

, and tryptophan hydroxylase together constitute the family of biopterin-dependent

aromatic amino acid hydroxylase Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic amino acid hydroxylase enzymes which includes phenylalanine 4-hydroxylase (), tyrosine 3-hydroxylase (), and tryptophan 5-hydroxylase (). These enzymes primaril ...

s. TPH catalyzes the following chemical reaction : L-

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...

+ O₂

\rightleftharpoons

5-Hydroxytryptophan 5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. 5-HTP can be manufactured and use ...

dihydrobiopterin Dihydrobiopterin (BH2) is a pteridine compound produced in the synthesis of L-DOPA, dopamine, serotonin, norepinephrine and epinephrine. It is restored to the required cofactor tetrahydrobiopterin by dihydrobiopterin reductase. See also * Pt ...

+ H₂O It employs one additional cofactor,

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

Function

It is responsible for addition of the -OH group (

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

) to the 5 position to form the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

5-hydroxytryptophan 5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. 5-HTP can be manufactured and use ...

(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 Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...

(TH) and

(PAH) are members of a superfamily of

s, catalyzing key steps in important metabolic pathways. Analogously to

and

, this enzyme uses (6R)-L-erythro-5,6,7,8-

(BH₄) and dioxygen as cofactors. In humans, the stimulation of serotonin production by administration of tryptophan has an antidepressant effect and inhibition of tryptophan hydroxylase (e.g. by p-Chlorophenylalanine) may precipitate depression. 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 In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

Protein Kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

, 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 Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the ''TPH1'' gene. TPH1 was first discovered to support serotonin synthesis in 1988 by converting tryptophan into 5-hydroxytryptophan. It w ...

'' and ''

TPH2 Tryptophan hydroxylase 2 (TPH2) is an isozyme of tryptophan hydroxylase found in vertebrates. In humans, TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain. Unt ...

'' (sequence identity 71%). * TPH1 is mostly expressed in tissues that express serotonin (a neurotransmitter) in the periphery (

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

, gut,

pineal gland The pineal gland (also known as the pineal body or epiphysis cerebri) is a small endocrine gland in the brain of most vertebrates. It produces melatonin, a serotonin-derived hormone, which modulates sleep, sleep patterns following the diurnal c ...

) but it is also expressed in the central nervous system. * On the other hand, TPH2 is exclusively expressed in

neuronal A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...

cell types and is the predominant isoform in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

Inhibitors

Tryptophan hydroxylase inhibitors include

fenclonine Fenclonine, also known as ''para''-chlorophenylalanine (PCPA), acts as a selective and irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin. It has been used experimentally to treat c ...

(''para''-chlorophenylalanine or PCPA) and

telotristat ethyl Telotristat ethyl (United States Adopted Name, USAN, brand name Xermelo) is a prodrug of telotristat, which is an inhibitor of tryptophan hydroxylase. It is formulated as telotristat etiprate — a Hippuric acid, hippurate salt of telotristat eth ...

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of telotristat).

Additional images

Image:5htsynt 2.png , The pathway for the synthesis of serotonin from tryptophan Image:Trp-5ht-pathway.svg , Metabolic pathway from tryptophan to serotonin

References

External links

* * See als
tryptophan hydroxylase
i
Proteopedia
EC 1.14.16 {{1.14-enzyme-stub