Biochemistry · Metabolic pathway

Catecholamine synthesis and breakdown !

The adrenal medulla and some neurons build dopamine, norepinephrine and epinephrine from tyrosine, then break them down to metanephrines and VMA.

Updated 2026-11-01

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Key facts

Tyrosine hydroxylase is the rate-limiting step; it needs BH4, Fe²⁺ and O₂ and is inhibited by its own catecholamine products.
DOPA decarboxylase (vitamin B6) is the target of carbidopa, which stops levodopa from being decarboxylated outside the brain.
Dopamine β-hydroxylase works inside the storage vesicles and needs copper and vitamin C.
PNMT is found mainly in the adrenal medulla, where cortisol arriving from the cortex through portal blood induces it.
COMT makes metanephrines, and MAO plus aldehyde dehydrogenase make VMA; plasma free metanephrines are the screening test for phaeochromocytoma.

Also called: Dopamine, norepinephrine and epinephrine synthesis

Regulation

Nerve impulses and stress activate tyrosine hydroxylase by phosphorylation (PKA, CaMK) within minutes and by making more enzyme over hours.
Dopamine and norepinephrine inhibit tyrosine hydroxylase by competing with BH4 (feedback).
Cortisol from the adrenal cortex induces PNMT, so epinephrine is made almost only in the adrenal medulla.

The steps, one by one

Step 1 · Tyrosine hydroxylase (TH) irreversible Tyrosine + Tetrahydrobiopterin + o2 → L-DOPA + Dihydrobiopterin (BH2) + H₂OAdds a hydroxyl to the ring of tyrosine to make L-DOPA; it is the slowest and most tightly controlled step.If it fails: Tyrosine hydroxylase deficiency: dopa-responsive dystonia or severe infantile parkinsonism; BH4 deficiencies also slow this step.
Step 2 · Aromatic L-amino acid decarboxylase (AADC, DOPA decarboxylase) irreversible L-DOPA → Dopamine + CO₂Removes the carboxyl group of L-DOPA to give dopamine; the same enzyme makes serotonin from 5-hydroxytryptophan.If it fails: Parkinson treatment depends on this step: brain AADC turns levodopa into dopamine while carbidopa blocks it outside the brain. AADC deficiency itself causes infantile hypotonia and oculogyric crises. Parkinson disease →
Step 3 · Dopamine β-hydroxylase (DBH) irreversible Dopamine + Vitamin C + o2 → Norepinephrine + Dehydroascorbate + H₂OInside the storage vesicles it adds a hydroxyl to the side chain of dopamine, giving norepinephrine.If it fails: DBH deficiency: no norepinephrine or epinephrine, with severe orthostatic hypotension; in Menkes disease low copper lowers DBH activity. Menkes disease →
Step 4 · Phenylethanolamine N-methyltransferase (PNMT) irreversible Norepinephrine + S-adenosylmethionine → Epinephrine (adrenaline) + S-AdenosylhomocysteineMoves a methyl group from SAM onto the amine of norepinephrine to give epinephrine, mainly in the adrenal medulla.If it fails: When cortisol is low, as in adrenal insufficiency, PNMT falls and the adrenal medulla makes less epinephrine. Adrenal insufficiency →
Step 5 · Catechol-O-methyltransferase (COMT) irreversible Epinephrine (adrenaline) + S-adenosylmethionine → Metanephrine + S-AdenosylhomocysteineMethylates the 3-hydroxyl of the catechol ring; inside tumour cells this makes metanephrine all the time.If it fails: Phaeochromocytomas contain COMT and leak metanephrines into the blood continuously, even between attacks of hypertension. Phaeochromocytoma →
Step 6 · Monoamine oxidase A, then aldehyde dehydrogenase irreversible Metanephrine + o2 + H₂O + NAD⁺ → Vanillylmandelic acid (VMA) + nh3 + NADHMAO removes the amine as ammonia and hydrogen peroxide, and aldehyde dehydrogenase oxidises the aldehyde to VMA, which leaves in the urine.If it fails: Urinary VMA and metanephrines rise in phaeochromocytoma and, in children, in neuroblastoma.

Clinical notes

Parkinson disease: dopaminergic neurons of the substantia nigra are lost; levodopa with carbidopa replaces dopamine in the brain.
Phaeochromocytoma: a chromaffin-cell tumour that releases catecholamines; it is diagnosed with plasma or urine metanephrines.
Metyrosine inhibits tyrosine hydroxylase and is used to block catecholamine synthesis before surgery for phaeochromocytoma.
MAO inhibitors taken with tyramine-rich foods can cause a hypertensive crisis.

Pathways

Catecholamine synthesis and breakdown

Test yourself

Think of the answer, then tap the question to see it.

Which step limits the rate of catecholamine synthesis?

Tyrosine hydroxylase, which needs BH4, Fe²⁺ and O₂ and is inhibited by dopamine and norepinephrine.

Why is levodopa given with carbidopa?

Carbidopa blocks DOPA decarboxylase outside the brain, so more levodopa reaches the brain and fewer peripheral effects of dopamine appear.

Why is epinephrine made almost only in the adrenal medulla?

PNMT is induced by the high cortisol that reaches the medulla from the cortex through the adrenal portal circulation.

Which test screens for phaeochromocytoma, and why?

Plasma free or urine fractionated metanephrines: COMT inside the tumour makes them continuously, so they are high even between attacks.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: TH gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Aromatic l-amino acid decarboxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Dopamine beta-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Phenylethanolamine N-methyltransferase (PNMT) - Homo sapiens (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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