A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis

Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, w hich is the first step in the biosynthesis of indoleamines (serotonin and m elatonin). Serotonin functions mainly as a neurotransmitter, whereas melato nin is the principal hormone secreted by the pineal gland. TPH belongs to t he family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict re quirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). D uring the last three years there has been a formidable increase in the amou nt of structural information about PAH and TH, which has provided new insig hts into the active site structure, the binding of substrates, inhibitors a nd pterins, as well as on the effect of disease-causing mutations in these hydroxylases. Although structural information about TPH is not yet availabl e, the high sequence homology between the three mammalian hydroxylases, not ably at the catalytic domains, and the similarity of the reactions that the y catalyze, indicate that they share a similar 3D-structure and a common ca talytic mechanism. Thus, we have prepared a model of the structure of TPH b ased on the crystal structures of TH and PAH. This structural model provide s a frame for understanding the specific interactions of TPH with L-tryptop han and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecho lamines. The interactions of these ligands with the enzyme are discussed fo cusing on the physiological and pharmacological regulation of serotonin bio synthesis, notably by tryptophan supplementation therapy and substitution t herapy with tetrahydrobiopterin analogues positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinson's dis ease patients (enzyme inhibition).