Stepwise biosynthesis of dopamine, norepinephrine, and epinephrine from L-tyrosine. The rate-limiting step is tyrosine hydroxylation (TH); the BH4 cofactor regenerates via DHPR + DHFR. Loss of nigrostriatal dopamine neurons is the proximate cause of Parkinson disease — levodopa replaces the missing precursor and bypasses TH. DBH and PNMT are restricted to noradrenergic/adrenergic neurons + the adrenal medulla.
Organ Systems
nervous
endocrine
Pathway Steps
l-tyrosine → levodopa — via tyrosine hydroxylase (TH) — rate-limiting; requires BH4 cofactor. Tyrosine hydroxylase is the rate-limiting, committed step for all catecholamines — feedback-inhibited by cytosolic catecholamines and acutely activated by phosphorylation (PKA/CaMKII). Its BH4 (tetrahydrobiopterin) cofactor is shared with tryptophan and phenylalanine hydroxylases, coupling dopamine, serotonin, and phenylalanine handling.
levodopa → dopamine — via aromatic L-amino acid decarboxylase (AADC / DDC) — also produces 5-HT from 5-HTP. AADC (DOPA decarboxylase) is fast and non-rate-limiting, and is the same enzyme that converts 5-HTP to serotonin. Since peripheral AADC would convert L-DOPA to dopamine before it crosses the blood–brain barrier, Parkinson’s therapy pairs L-DOPA with a peripheral AADC inhibitor (carbidopa or benserazide).
dopamine → norepinephrine — via dopamine β-hydroxylase (DBH) — copper-dependent; ascorbate cofactor. Dopamine β-hydroxylase acts inside synaptic vesicles, is copper-dependent, and consumes ascorbate (vitamin C) as the electron donor. It is expressed only in noradrenergic and adrenergic cells, so dopaminergic neurons that lack DBH stop at dopamine.
norepinephrine → epinephrine — via phenylethanolamine N-methyltransferase (PNMT) — SAMe-dependent. Restricted to adrenal medulla + brainstem PNMT-expressing neurons.
Known Modulators
levodopa (substrate) — AADC step. Bypasses TH; clinically combined with carbidopa (peripheral AADC inhibitor) to prevent premature peripheral conversion.
selegiline (inhibitor) — downstream MAO-B (dopamine catabolism). Not a synthesis step but raises endogenous dopamine pool by blocking degradation. Listed for pathway-level surfacing.