Mechanisms of tryptophan and tyrosine hydroxylase

The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine hydroxylase are responsible for the initial steps in the formation of serotonin and the catecholamine neurotransmitters, respectively. Both enzymes are nonheme iron-dependent monooxygenases that catalyze the insertion of one atom of molecular oxygen onto the aromatic ring of their amino acid substrates, using a tetrahydropterin as a two electron donor to reduce the second oxygen atom to water. This review discusses the current understanding of the catalytic mechanism of these two enzymes. The reaction occurs as two sequential half reactions: a reaction between the active site iron, oxygen, and the tetrahydropterin to form a reactive Fe^IVO intermediate and hydroxylation of the amino acid by the Fe^IVO. The mechanism of formation of the Fe^IVO is unclear; however, considerable evidence suggests the formation of an Fe^II-peroxypterin intermediate. The amino acid is hydroxylated by the Fe^IVO intermediate in an electrophilic aromatic substitution mechanism.