[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Serotonin and melatonin synthesis [Biochemistry](https://durgical.com/en/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 ## Interactive map ## 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](https://durgical.com/en/biochemistry/molecules/tryptophan/) + [Tetrahydrobiopterin](https://durgical.com/en/biochemistry/molecules/tetrahydrobiopterin/) + o2 → 5-Hydroxytryptophan (5-HTP) + Dihydrobiopterin (BH2) + H₂O Adds 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) →](https://durgical.com/en/conditions/pellagra/) - **Step 2 · Aromatic L-amino acid decarboxylase (AADC)** irreversible 5-Hydroxytryptophan (5-HTP) → [Serotonin](https://durgical.com/en/biochemistry/molecules/serotonin/) + CO₂ Removes 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 →](https://durgical.com/en/conditions/carcinoid-syndrome/) - **Step 3 · Serotonin N-acetyltransferase (AANAT)** irreversible [Serotonin](https://durgical.com/en/biochemistry/molecules/serotonin/) + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) → N-Acetylserotonin + coenzyme A In 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](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/) → [Melatonin](https://durgical.com/en/biochemistry/molecules/melatonin/) + [S-Adenosylhomocysteine](https://durgical.com/en/biochemistry/molecules/s-adenosylhomocysteine/) Methylates 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 - [Serotonin and melatonin synthesis](https://durgical.com/en/biochemistry/pathways/serotonin-and-melatonin-synthesis/) ## Related conditions - [Carcinoid syndrome](https://durgical.com/en/conditions/carcinoid-syndrome/) - [Pellagra (niacin deficiency)](https://durgical.com/en/conditions/pellagra/) - [Hartnup disease](https://durgical.com/en/conditions/hartnup-disease/) ## Related - [Tryptophan](https://durgical.com/en/biochemistry/molecules/tryptophan/) - [Serotonin (5-hydroxytryptamine)](https://durgical.com/en/biochemistry/molecules/serotonin/) - [Melatonin](https://durgical.com/en/biochemistry/molecules/melatonin/) - [Tetrahydrobiopterin (BH4)](https://durgical.com/en/biochemistry/molecules/tetrahydrobiopterin/) - [Niacin (vitamin B3)](https://durgical.com/en/biochemistry/molecules/niacin/) - [Vitamin B6 (pyridoxal phosphate)](https://durgical.com/en/biochemistry/molecules/vitamin-b6/) - [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) - [S-adenosylmethionine (SAM)](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/) - [Molecules derived from amino acids](https://durgical.com/en/biochemistry/topics/molecules-derived-from-amino-acids/) - [Catecholamine synthesis and breakdown](https://durgical.com/en/biochemistry/pathways/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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/serotonin-and-melatonin-synthesis/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [Carcinoid syndrome: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/000347.htm) (MedlinePlus, US National Library of Medicine, 2026); [5-HIAA urine test: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/003612.htm) (MedlinePlus, US National Library of Medicine, 2026); [Tryptophan 5-hydroxylase 1 (TPH1) - Homo sapiens](https://www.uniprot.org/uniprotkb/P17752/entry) (UniProt, 2026); [Acetylserotonin O-methyltransferase (ASMT) - Homo sapiens](https://www.uniprot.org/uniprotkb/P46597/entry) (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/pathways/serotonin-and-melatonin-synthesis/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/serotonin-and-melatonin-synthesis/