Catecholamine biosynthesis (Tyr -> L-DOPA -> dopamine -> noradrenaline -> adrenaline)

The catecholamine neurotransmitters and hormones - dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) - are synthesised from the amino acid L-tyrosine by a linear four-enzyme pathway operating in catecholaminergic neurons and adrenal chromaffin cells. Tyrosine hydroxylase (TH), the rate-limiting enzyme, hydroxylates L-tyrosine to L-DOPA using tetrahydrobiopterin (BH4), O2 and a non-heme Fe(II) centre. Aromatic L-amino-acid decarboxylase (DDC/AADC), a pyridoxal-phosphate enzyme, decarboxylates L-DOPA to dopamine (and, on the parallel indoleamine branch, 5-HTP to serotonin). In noradrenergic and adrenergic cells, dopamine is imported into secretory (chromaffin) granules, where the copper- and ascorbate-dependent dopamine beta-hydroxylase (DBH) hydroxylates it to noradrenaline; finally, in adrenal medullary and some central adrenergic cells, the SAM-dependent phenylethanolamine N-methyltransferase (PNMT) N-methylates noradrenaline to adrenaline. Which product predominates depends on the cell type's enzyme complement (dopaminergic cells stop at dopamine; noradrenergic add DBH; adrenergic add PNMT). Inherited defects are severe neurological/autonomic disorders: TH deficiency causes DOPA-responsive dystonia / infantile parkinsonism, AADC (DDC) deficiency a global monoamine-neurotransmitter disease, and DBH deficiency autosomal-recessive orthostatic hypotension.