Biochemistry · Metabolic pathway
Serotonin and melatonin synthesis !
Tryptophan becomes serotonin in the gut and brain, and serotonin becomes melatonin in the pineal gland at night.
Updated 2026-11-01
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Key facts
- Tryptophan hydroxylase is the rate-limiting step: TPH1 in enterochromaffin cells and the pineal gland, TPH2 in brain neurons; both need BH4.
- The same aromatic L-amino acid decarboxylase (B6) that makes dopamine turns 5-hydroxytryptophan into serotonin.
- About 90% of the body's serotonin is made in the gut and carried by platelets; it does not cross the blood–brain barrier.
- MAO-A breaks serotonin down to 5-HIAA, which is measured in urine to look for carcinoid tumours.
- In the pineal gland darkness raises AANAT activity through norepinephrine and cAMP, so melatonin peaks at night.
Regulation
- Tryptophan supply limits TPH, which is not saturated by its substrate; other large neutral amino acids compete with tryptophan to enter the brain.
- Night-time norepinephrine from sympathetic fibres raises cAMP in pinealocytes and activates AANAT; light at night quickly switches it off.
- Phosphorylation by PKA activates TPH.
The steps, one by one
- Step 1 · Tryptophan hydroxylase (TPH1 gut and pineal, TPH2 brain) irreversible Tryptophan + Tetrahydrobiopterin + o2 → 5-Hydroxytryptophan (5-HTP) + Dihydrobiopterin (BH2) + H₂OAdds a hydroxyl at position 5 of the indole ring of tryptophan; this is the controlled step.If it fails: In carcinoid tumours TPH1 works flat out; tryptophan is diverted away from niacin synthesis and pellagra can follow. Pellagra (niacin deficiency) →
- Step 2 · Aromatic L-amino acid decarboxylase (AADC) irreversible 5-Hydroxytryptophan (5-HTP) → Serotonin + CO₂Removes the carboxyl of 5-HTP to give serotonin (5-hydroxytryptamine), which is stored in vesicles and in platelets.If it fails: Carcinoid tumours overproduce serotonin: flushing, diarrhoea, wheezing and right-sided valve fibrosis, with high urinary 5-HIAA. Carcinoid syndrome →
- Step 3 · Serotonin N-acetyltransferase (AANAT) irreversible Serotonin + Acetyl-CoA → N-Acetylserotonin + coenzyme AIn the pineal gland it adds an acetyl group from acetyl-CoA to serotonin; its activity rises many times over in darkness.If it fails: Light at night, shift work and jet lag lower AANAT activity and melatonin, and disturb the sleep–wake rhythm.
- Step 4 · Acetylserotonin O-methyltransferase (ASMT, HIOMT) irreversible N-Acetylserotonin + S-adenosylmethionine → Melatonin + S-AdenosylhomocysteineMethylates the 5-hydroxyl group and produces melatonin, which passes straight from the pineal gland into the blood and CSF.If it fails: Pineal tumours or lesions can abolish the night-time rise of melatonin.
Clinical notes
- Carcinoid syndrome: a neuroendocrine tumour, usually with liver metastases, releases serotonin and causes flushing, diarrhoea and right-heart valve disease; urinary 5-HIAA is high.
- In carcinoid syndrome so much tryptophan goes to serotonin that niacin synthesis falls and pellagra may appear.
- SSRIs block serotonin reuptake; combined with MAO inhibitors they can cause serotonin syndrome.
- Telotristat, a peripheral TPH1 inhibitor, reduces carcinoid diarrhoea.
Pathways
Related conditions
Related
- Tryptophan
- Serotonin (5-hydroxytryptamine)
- Melatonin
- Tetrahydrobiopterin (BH4)
- Niacin (vitamin B3)
- Vitamin B6 (pyridoxal phosphate)
- Acetyl-CoA
- S-adenosylmethionine (SAM)
- Molecules derived from amino acids
- Catecholamine synthesis and breakdown
Test yourself
Think of the answer, then tap the question to see it.
Which enzyme is shared by serotonin and dopamine synthesis?
Aromatic L-amino acid decarboxylase (DOPA decarboxylase), which needs vitamin B6.
Why can carcinoid syndrome cause pellagra?
The tumour diverts a large share of dietary tryptophan into serotonin, leaving too little to make niacin (NAD⁺).
Which urine metabolite is measured for carcinoid tumours?
5-HIAA (5-hydroxyindoleacetic acid), made when MAO-A and aldehyde dehydrogenase break down serotonin.
Why does melatonin rise at night?
In darkness sympathetic fibres release norepinephrine on the pineal gland; cAMP activates AANAT, the controlling step for melatonin.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Carcinoid syndrome: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); 5-HIAA urine test: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Tryptophan 5-hydroxylase 1 (TPH1) - Homo sapiens (UniProt, 2026); Acetylserotonin O-methyltransferase (ASMT) - 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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