Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study

Serotonin is a hormone that is responsible for mood-swings in the brain; yet details on its biosynthetic mechanism remains controversial. Tryptophan hydroxylase catalyzes the first step in the serotonin biosynthesis in the human body where it regio- and stereo selectively hydroxylates a free Trp amino acid at the C5-position. In this work we present a computational study ranging from molecular dynamics to quantum mechanics methods focused on the tryptophan
hydroxylase mechanism. An MD simulation on an enzymatic structure with substrate, co-substrate and dioxygen bound reveals a tight binding conformation of substrate and co-substrate, while the protein three-dimensional structure stays virtually intact during the simulation. Subsequently, large active site cluster models were created of more than 200 atoms and the oxygen atom transfer reactions were studied. The calculations predict that co-factor tetrahydrobiopterin binds covalently to the iron center and react with a molecule of dioxygen to form an iron(IV)-oxo species and pterin-4a-carbinolamine in a
stepwise manner with small barriers (<5 kcal mol−1) and an exergonic
pathway. The rate-determining step, however, is Trp activation through a C−O activation transition state followed by rapid proton relay to form 5-hydroxy-L-Trp products.