Tyrosine hydroxylase (TyrH) is the rate-limiting enzyme in catecholamine biosynthesis, converting tyrosine to dopamine (DOPA). Its activity is regulated by phosphorylation by multiple kinases at four serine residues and dephosphorylation by phosphatases. Catecholamine neurotransmitters inhibit TyrH through feedback mechanisms. Dopamine competitively binds to TyrH with tetrahydrobiopterin and interacts with the R domain. TyrH activity is modulated by interactions with enzymes in the tetrahydrobiopterin pathway, structural proteins, and vesicular monoamine transporter (VMAT). TyrH is also modified by nitration and glutathionylation in the presence of nitric oxide (NO). The R domain of TyrH is involved in regulation, with phosphorylation affecting its structure and activity. Human TyrH has four isoforms with different R domain sequences, each with distinct affinities for DOPA and dopamine. TyrH forms complexes with 14-3-3 proteins, α-synuclein, PP2A, AADC, GTP cyclohydrolase, VMAT, and DJ-1, potentially influencing enzyme localization and activity. Nitration of TyrH by peroxynitrite inactivates the enzyme, reflecting oxidative stress in Parkinson's disease.Tyrosine hydroxylase (TyrH) is the rate-limiting enzyme in catecholamine biosynthesis, converting tyrosine to dopamine (DOPA). Its activity is regulated by phosphorylation by multiple kinases at four serine residues and dephosphorylation by phosphatases. Catecholamine neurotransmitters inhibit TyrH through feedback mechanisms. Dopamine competitively binds to TyrH with tetrahydrobiopterin and interacts with the R domain. TyrH activity is modulated by interactions with enzymes in the tetrahydrobiopterin pathway, structural proteins, and vesicular monoamine transporter (VMAT). TyrH is also modified by nitration and glutathionylation in the presence of nitric oxide (NO). The R domain of TyrH is involved in regulation, with phosphorylation affecting its structure and activity. Human TyrH has four isoforms with different R domain sequences, each with distinct affinities for DOPA and dopamine. TyrH forms complexes with 14-3-3 proteins, α-synuclein, PP2A, AADC, GTP cyclohydrolase, VMAT, and DJ-1, potentially influencing enzyme localization and activity. Nitration of TyrH by peroxynitrite inactivates the enzyme, reflecting oxidative stress in Parkinson's disease.