tyrosine hydroxylase

Tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step in the synthesis of catecholamines: dopamine, norepinephrine, and epinephrine. It hydroxylates L-tyrosine to form L-DOPA, requiring molecular oxygen and tetrahydrobiopterin (BH4) as a cofactor. This step is followed by DOPA decarboxylase (aromatic L-amino acid decarboxylase) converting L-DOPA to dopamine, which can then be converted to norepinephrine by dopamine β-hydroxylase, and finally to epinephrine by phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla.

Regulation: TH activity is tightly controlled by feedback inhibition from catecholamines (competitive with BH4 binding) and by phosphorylation via PKA, PKC, and CaMKII, which increases enzyme activity in response to neuronal stimulation (e.g., stress, sympathetic activation). Long-term regulation occurs via increased TH gene transcription during chronic stress.

Clinical significance: - TH is used as an immunohistochemical marker for catecholaminergic neurons and neuroendocrine tumors (e.g., pheochromocytoma, neuroblastoma, paraganglioma) since these tumors often stain positive for TH and chromogranin A. - TH deficiency causes a rare autosomal recessive disorder leading to L-DOPA-responsive dystonia or infantile parkinsonism, presenting with hypotonia, dystonia, and developmental delay due to insufficient dopamine/norepinephrine synthesis. - Loss of dopaminergic neurons (and thus TH-positive neurons) in the substantia nigra is characteristic of Parkinson disease. - Pharmacologic relevance: metyrosine (alpha-methyl-tyrosine) is a competitive inhibitor of TH used to manage catecholamine excess in pheochromocytoma before surgery.

Understanding TH is essential for grasping catecholamine synthesis pathways, related genetic disorders, and pharmacologic interventions targeting this pathway.