P.1.a.008 Catechol-O-methyltrasferase gene polymorphism (Val/Met) is not associated with bipolar disorder

Abstract

Potential determinants of existing tryptophan hydroxylase (TPH) activity in vivo are (1) a supply of tryptophan via the tryptophan transporter, (2) de novo synthesis of tetrahydrobiopterin and efficient regeneration of this coenzyme, and (3) iron metabolism. TPH is an iron protein. Iron binding is relatively strong in TPH2, while it is very weak in TPH1. Owing to the poorly liganded iron of TPH, various complexities arise. Irreversible inactivation of TPH and neural deterioration seem to be caused by an H2O2 reaction with non-liganded or poorly liganded Fe2+. Within the cell, the amount of ferrous iron available to TPH is below saturation. The metabolism of iron may control serotonin production by attenuating actual TPH activity in the cell interior. Phosphorylation of TPH was studied in terms of its functional aspects with the use of brain TPH, while the identification of phosphorylation sites was mainly conducted on the basis of the amino acid sequence of TPH1. Protein turnover is cell-type specific in terms of its machinery, and its regulation is one of the major post-translational modifications of a protein. TPH degradation is likely linked to protein phosphorylation. Functionally, TPH, the rate-limiting enzyme in serotonin biosynthesis, is involved in neural development, which likely affects animal behaviors in the adult stages. Future studies will define the sensitive period during development when TPH activity is required for the fine-tuning of neuronal organization that is responsible for each behavior in the adult.