TPH belongs to the superfamily of aromatic amino acid hydroxylases which also includes tyrosine hydroxylase and phenylalanine hydroxylase (PAH). 5-HT is synthesized by two tryptophan hydroxylases, TPH1 in ECs of the gut and TPH2 in hindbrain raphe nuclei. EC-derived 5-HT is transported by circulating platelets and released upon their activation. TPH1 and TPH2 are highly homologous proteins, but differ in their kinetic properties and, more notably, in their tissue distribution. TPH2 is predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut, and is considered to be the source of the central neurotransmitter pool of 5-HT. The majority of blood 5-HT is synthesized by TPH1-expressing ECs of the gastrointestinal (GI) tract and enters the circulation packed in dense granules of thrombocytes where it mediates its hormonal actions upon platelet release at the site of activation. 
TPH1 is also found in other peripheral tissues such as pancreas, fat, and lung, as well as in the pineal gland where 5-HT serves as a precursor molecule for melatonin biosynthesis. Therapeutics involving the serotonergic system only targeted 5-HT transporters and receptors, and were mostly aimed at central indications such as depression, psychosis, and migraine.The dualistic character of the 5-HT system, enforced by the inability of 5-HT to freely cross the blood–brain barrier in either direction, gave rise to the opportunity to pharmacologically target central and peripheral 5-HT biosynthesis in an independent manner.


1.Matthes S, et al. Trends Pharmacol Sci. 2018;39(6):560–572.