Tryptophan hydroxylase

Tryptophan hydroxylase (TPH) is an enzyme involved in the synthesis of the neurotransmitter serotonin.

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 then converted to serotonin by decarboxylation:

Analogous to phenylalanine hydroxylase and tyrosine hydroxylase, this enzyme uses tetrahydrobiopterin as a co-substrate.

Tryptophan can cross the Blood-brain barrier, while Serotonin cannot. For this reason, tryptophan is administered when the desired effect is to have larger amounts of serotonin in the brain.

The "activity" of tryptophan hydroxylase (i.e. the rate 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. This phosphorylation is of particular interest, because in the 2 major steps to serotonin production (L-tryptophan to L-5-hydroxytryptophan to 5-hydroxytryptamine [serotonin]), the first step - involving tryptophan hydroxylase - is the rate limiting step.

Isoforms
In humans, as well as in other mammals, there are two isoforms of this enzyme. These isoforms are termed 1 and 2 and derive from two different, but homologous, genes.
 * TPH1 is mostly expressed in tissues that express serotonin 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.