Tryptophan hydroxylase (
TPH) is an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
involved in the synthesis of the neurotransmitter
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
. TPH catalyzes the following chemical reaction
- L-tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
+ tetrahydrobiopterinTetrahydrobiopterin or sapropterin, is a naturally occurring nutrient and essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine , epinephrine , and nitric oxide...
+ O2 5-Hydroxytryptophan5-Hydroxytryptophan is a naturally occurring amino acid, a precursor to the neurotransmitter serotonin and an intermediate in tryptophan metabolism. It is marketed in the United States and other countries as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid...
+ 4a-hydroxytetrahydrobiopterin
It employs one
cofactorA cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes and cofactors can be considered "helper molecules/ions" that assist in biochemical transformations...
,
ironIron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
.
It is responsible for addition of the -HO group (
hydroxylationHydroxylation is any chemical process that introduces one or more hydroxyl groups into a compound thereby oxidizing it. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases....
) to the 5 position to form the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
5-hydroxytryptophan5-Hydroxytryptophan is a naturally occurring amino acid, a precursor to the neurotransmitter serotonin and an intermediate in tryptophan metabolism. It is marketed in the United States and other countries as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid...
(5-HTP), which is the initial and rate-limiting step in the synthesis of the neurotransmitter serotonin.
Tryptophan hydroxylase (
TPH) is an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
involved in the synthesis of the neurotransmitter
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
. TPH catalyzes the following chemical reaction
- L-tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
+ tetrahydrobiopterinTetrahydrobiopterin or sapropterin, is a naturally occurring nutrient and essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine , epinephrine , and nitric oxide...
+ O2 5-Hydroxytryptophan5-Hydroxytryptophan is a naturally occurring amino acid, a precursor to the neurotransmitter serotonin and an intermediate in tryptophan metabolism. It is marketed in the United States and other countries as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid...
+ 4a-hydroxytetrahydrobiopterin
It employs one
cofactorA cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes and cofactors can be considered "helper molecules/ions" that assist in biochemical transformations...
,
ironIron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
.
Function
It is responsible for addition of the -HO group (
hydroxylationHydroxylation is any chemical process that introduces one or more hydroxyl groups into a compound thereby oxidizing it. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases....
) to the 5 position to form the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
5-hydroxytryptophan5-Hydroxytryptophan is a naturally occurring amino acid, a precursor to the neurotransmitter serotonin and an intermediate in tryptophan metabolism. It is marketed in the United States and other countries as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid...
(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. Analogously to
phenylalanine hydroxylasePhenylalanine hydroxylase is an enzyme which catalyses the reaction responsible for the addition of an hydroxyl group to the end of the 6-carbon aromatic ring of phenylalanine, such that it becomes tyrosine:...
and
tyrosine hydroxylaseTyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . DOPA is a precursor for dopamine which in turn is a precursor for norepinephrine and epinephrine...
, this enzyme uses (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH
4) 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
phosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many protein enzymes on and off, causing or preventing the mechanisms of diseases such as cancer and diabetes....
. 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%).
- TPH1 is mostly expressed in tissues that express serotonin (a neurotransmitter) in the periphery (skin
The skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system made up of multiple layers of mesodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs. Skin of a different nature exists in amphibians, reptiles, birds...
, gut, pineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces melatonin, a hormone that affects the modulation of wake/sleep patterns and photoperiodic functions...
) 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
The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
.
- Tryptophan may be found in foods such as fresh fruits and fresh vegetables as well as dark chocolate (natural cocoa).
External links
See also
tryptophan hydroxylase in
Proteopedia