Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis; it uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to DOPA. Its amino-terminal 150 amino acids comprise a domain whose structure is involved in regulating the activity of the enzyme.
Modes of regulation include phosphorylation by multiple kinases at 4 different serine residues and dephosphorylation by 2 phosphatases. The enzyme is feedback inhibited by catecholamine neurotransmitters. Dopamine binds to TyrH competitively with tetrahydrobiopterin and interacts with the R domain.
TyrH activity is modulated by protein-protein interactions with enzymes in the same or the tetrahydrobiopterin pathway, with structural proteins that are chaperones and mediate the oxidative state of the neuron, and with the protein that transfers dopamine to secretory vesicles. TyrH is modified in the presence of NO, leading to nitration of tyrosine residues and glutathionylation of cysteine residues.