Serotonintransporter-Genetik (5-HTT/SERT, 5-HTTLPR): the pathway in the body

Serotonintransporter-Genetik (5-HTT/SERT, 5-HTTLPR) is part of the pathway “Serotonin and melatonin”. This page shows the whole pathway; the station of Serotonintransporter-Genetik (5-HTT/SERT, 5-HTTLPR) is highlighted.

Where this laboratory value sits: Reuptake — transporter SERT. The transporter SERT carries serotonin from the gap between cells back inside. The signal ends there; the same protein also brings serotonin into blood platelets. The faster SERT works, the shorter serotonin acts. Source 11

In brief

Serotonin and melatonin are messengers that the body makes from the amino acid tryptophan. Serotonin is formed in the gut lining and in nerve cells, melatonin at night in the pineal gland. Only a small part of the tryptophan follows this route. Light slows melatonin formation.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Tryptophan → 5-Hydroxytryptophan TPH1, TPH2 · BH4, Iron Tryptophan hydroxylase attaches an OH group to tryptophan. The enzyme carries iron and works with tetrahydrobiopterin (BH4) and oxygen. Two forms exist: TPH1 in the gut, TPH2 in nerve cells. This step is the slowest of the route. It sets the pace. Source 1, 7↑ supplies 5-HTP is the precursor just one step away from serotonin. Because tryptophan hydroxylase works slowly and needs BH4, iron and oxygen, this step determines how much serotonin can form at all. established physiology Source 1, 7
   ⚖ When the balance tips

   too much — If more 5-HTP forms, AADC quickly converts it on to serotonin; it hardly accumulates, because the following step runs faster than this one.

   too little — If little BH4 is available, tryptophan hydroxylase works more slowly and less 5-HTP forms; the same BH4 is also needed by the hydroxylase for dopamine and for making nitric oxide.

   established physiology · Source 1, 2, 7

2. 5-Hydroxytryptophan → Serotonin AADC · Vitamin B6 (PLP) The enzyme AADC removes a carboxyl group from 5-HTP, using pyridoxal phosphate, the active form of vitamin B6. Serotonin is formed separately in two places: in the enterochromaffin cells of the gut lining and in nerve cells of the brain. Source 2, 3↕ both, depending on amount Serotonin is a messenger in many places: in the gut it stimulates movement of the gut wall, in vessels it narrows or widens them, in the brain it carries signals between nerve cells. Depending on the receptor, the same amount excites or dampens. established physiology Source 3, 11
   ⚖ When the balance tips

   too much — If serotonin builds up in the gap between cells, more receptors are occupied for longer; monoamine oxidase then breaks down more of it, and more 5-HIAA appears in the urine.

   too little — If little serotonin is available, the 5-HT receptors are occupied less often, and the pineal gland has less starting material for melatonin.

   established physiology · Source 11, 6

3. Serotonin → N-Acetylserotonin AANAT · Acetyl-CoA In the pineal gland, the enzyme AANAT attaches an acetyl group to serotonin at night. The amount of this enzyme follows the day-night rhythm. Light slows AANAT, which makes melatonin a night-time signal. Source 4↑ supplies N-acetylserotonin is the direct precursor of melatonin. Because AANAT is made in large amounts at night and broken down quickly in light, this step sets when melatonin forms. established physiology Source 4
   ⚖ When the balance tips

   too much — If AANAT runs fully at night in darkness, a lot of N-acetylserotonin forms; ASMT converts it to melatonin, and the night-time rise is high.

   too little — If light falls on the retina at night, AANAT is slowed; little N-acetylserotonin then forms, and the night-time rise in melatonin is smaller.

   established physiology · Source 4

4. N-Acetylserotonin → Melatonin ASMT · SAM The enzyme ASMT transfers a methyl group from SAM to N-acetylserotonin. Melatonin leaves the pineal gland and spreads through the body via the blood. Its rise in the blood is the night-time signal. Source 4↑ supplies Melatonin is the time signal of the night: its level in the blood rises with darkness and falls in the morning. Via MT1 and MT2 it tells the inner clock and many tissues that it is night, and lowers body temperature slightly. established physiology Source 4
   ⚖ When the balance tips

   too much — If there is a lot of melatonin in the blood during the day, the night signal arrives at the wrong time; the inner clock then shifts, forward or backward depending on the timing.

   too little — If the night-time rise is small, for example with light at night, the inner clock receives a weaker night signal, and the day-night rhythm of the tissues is tuned less clearly.

   established physiology · Source 4

5. Melatonin → Melatonin receptors Melatonin binds the receptors MT1 and MT2. They sit, among other places, in the suprachiasmatic nucleus, the inner clock of the brain, and on vessels and further tissues. Through them, the night signal reaches the inner clock. Source 4↑ supplies Via MT1 and MT2, melatonin acts as a night signal: at the inner clock MT1 dampens the nerve cells and MT2 shifts the clock's timing; on vessels they narrow or widen them depending on the type. established physiology Source 4
   ⚖ When the balance tips

   too much — If the receptors are strongly occupied at the wrong time of day, MT2 shifts the inner clock; depending on the timing, it then runs earlier or later.

   too little — If the receptors are occupied little at night, the signal to the inner clock stays weak, and the nerve cells there are dampened less.

   established physiology · Source 4

6. 6-Hydroxymelatonin → 6-Sulfatoxymelatonin Sulfotransferase A sulfotransferase attaches a sulphate group to 6-hydroxymelatonin. In this water-soluble form, the compound leaves the body in the urine. Its amount reflects night-time melatonin formation. Source 4↓ depletes The sulphate group makes the breakdown product water-soluble so that the kidney can excrete it. The amount in the urine over one night reflects how much melatonin was formed during that time. established physiology Source 4
   ⚖ When the balance tips

   too much — If a lot of melatonin was formed at night, a lot of 6-sulphatoxymelatonin also appears in the urine in the morning; the compound itself no longer acts as a time signal.

   too little — If little melatonin was formed at night, for example with light at night, less 6-sulphatoxymelatonin is found in the urine in the morning.

   established physiology · Source 4

7. 5-HT receptors → Reuptake SERT The transporter SERT carries serotonin from the gap between cells back inside. The signal ends there; the same protein also brings serotonin into blood platelets. The faster SERT works, the shorter serotonin acts. Source 11↓ depletes SERT ends the serotonin signal by bringing the messenger back from the gap; inside the cell it is reused or broken down by MAO. The faster SERT works, the shorter serotonin acts at the receptors. established physiology Source 11
   ⚖ When the balance tips

   too much — If SERT works faster, serotonin is cleared from the gap more quickly, and the receptors are occupied for a shorter time.

   too little — If SERT is inhibited, serotonin stays in the gap longer and occupies the receptors longer; the platelets then absorb less serotonin.

   established physiology · Source 11, 3

Further stations

• Tryptophan — amino acid from food Tryptophan is an amino acid the body does not form itself. From dietary protein it enters the blood and follows three routes there: the kynurenine pathway, the route to serotonin and melatonin, and the bacterial route to indole. The routes share one pool. Source 3, 5, 8↑ supplies Tryptophan is the starting material for serotonin and melatonin. It shares its pool with the kynurenine pathway, protein synthesis and gut bacteria; if one of these routes is used more, less remains for the others. established physiology Source 5, 10, 3
  ⚖ When the balance tips

  too much — More tryptophan in the blood does not bring unlimited serotonin: at the blood-brain barrier it shares the transporter with other large amino acids, and the hydroxylase is the slowest step. Much of it runs into the kynurenine pathway.

  too little — If little tryptophan arrives, several routes share a smaller pool; in the brain the hydroxylase then has less starting material, and less serotonin forms.

  established physiology · Source 10, 5, 1

• Kynurenine pathway — second route of tryptophan Most tryptophan does not head towards serotonin but into the kynurenine pathway. There, the enzymes TDO and IDO open the ring part of the molecule. The more this pathway runs, the less tryptophan remains for serotonin. Source 5↓ depletes The kynurenine pathway draws off most of the tryptophan. The harder TDO in the liver or IDO in immune cells work, the less tryptophan remains for serotonin and melatonin. established physiology Source 5, 9
  ⚖ When the balance tips

  too much — If cells make more IDO in response to inflammatory signals, more tryptophan runs into this pathway; tryptophan in the blood falls, and less starting material remains for serotonin formation.

  too little — If TDO and IDO run more slowly, more tryptophan stays in the blood and more of it is available for protein synthesis and serotonin; the formation of NAD⁺ from tryptophan then declines.

  established physiology · Source 9, 5

• 5-HIAA — 5-hydroxyindoleacetic acid Monoamine oxidase (MAO) breaks serotonin down via an aldehyde intermediate. An aldehyde dehydrogenase turns this into 5-HIAA, which is excreted in the urine. This ends serotonin's action. Source 6↓ depletes The formation of 5-HIAA ends serotonin's action: MAO breaks it down, and the breakdown product no longer acts at the receptors. The amount in the urine reflects how much serotonin the body has broken down in total. established physiology Source 6, 3
  ⚖ When the balance tips

  too much — If a lot of serotonin is formed, for example in the gut, more also runs through MAO and more 5-HIAA appears in the urine. The reaction also produces hydrogen peroxide and an aldehyde, which the cell has to break down further.

  too little — If MAO works more slowly, serotonin persists longer and occupies its receptors for longer; less 5-HIAA forms.

  established physiology · Source 6, 3

• 6-Hydroxymelatonin — in the liver In the liver, the enzyme CYP1A2 attaches an OH group to melatonin. In this way the liver clears melatonin quickly from the blood. Source 4↓ depletes The OH group is the first step by which the liver clears melatonin from the blood. Because CYP1A2 works quickly, melatonin stays in the blood only briefly, and its level closely follows formation in the pineal gland. established physiology Source 4
  ⚖ When the balance tips

  too much — If CYP1A2 works faster, melatonin is cleared from the blood more quickly, and the night signal is shorter.

  too little — If CYP1A2 works more slowly, for example because other substances occupy the enzyme, melatonin stays in the blood longer, and the night signal lasts longer.

  established physiology · Source 4

• Indole route — by gut bacteria Bacteria in the large intestine split tryptophan with the enzyme tryptophanase. Indole and related substances arise; they bind the aryl hydrocarbon receptor of the gut lining and leave the body in urine. This branch draws on the tryptophan pool. Source 8↕ both, depending on amount The indole route diverts tryptophan in the gut before it reaches the blood. Indoles act via the aryl hydrocarbon receptor on the gut lining and its immune cells; in animal models they thus keep the mucosal barrier tight. observed in studies Source 8
  ⚖ When the balance tips

  too much — If bacteria convert a lot of tryptophan to indole, less of it is available for uptake into the blood. In the liver, indole is converted to indoxyl sulphate, which is excreted via the kidney.

  too little — If the gut bacteria make little indole, the aryl hydrocarbon receptor of the gut lining receives less signal; in animal models the mucosal barrier then becomes more permeable.

  observed in studies · Source 8

• Serotonin in blood — stored in blood platelets Most of the serotonin comes from the gut. Blood platelets absorb it through the transporter SERT and store it. Serotonin does not cross the blood-brain barrier; the brain forms its own. At injuries, the platelets release it. Source 3↑ supplies Blood platelets collect serotonin and release it when they attach to an injured vessel wall. There it narrows small vessels and attracts further platelets; in this way it contributes to stopping bleeding. established physiology Source 3, 11
  ⚖ When the balance tips

  too much — If the gut releases a lot of serotonin into the blood, the platelets absorb more of it until their store is full; what remains free in the blood is broken down via MAO to 5-HIAA.

  too little — If the platelets contain little serotonin, for example when SERT is inhibited, they release less of it at an injury; the narrowing of small vessels and the attraction of further platelets are weaker.

  established physiology · Source 3, 11, 6

• 5-HT receptors — binding sites Serotonin acts through a family of receptors, 5-HT1 to 5-HT7. Most pass the signal on through G proteins; 5-HT3 is an ion channel. They sit in the gut wall, on vessels and in nerve cells. The receptor decides whether it excites or dampens. Source 11↕ both, depending on amount The receptor decides what effect serotonin has: some types dampen the cell, others excite it, and 5-HT3, as an ion channel, lets ions flow in directly. The same amount of serotonin can thus excite in one place and slow things in another. established physiology Source 11
  ⚖ When the balance tips

  too much — If the receptors are strongly occupied, the processes they control run more strongly: the gut wall moves faster, vessels narrow or widen, and nausea arises via 5-HT3.

  too little — If the receptors are occupied little, these signals are weaker; in the gut, for example, the wall moves more slowly.

  established physiology · Source 11, 3

Cofactors in this pathway

• Tetrahydrobiopterin (BH4) — Cofactor of tryptophan hydroxylase, which forms 5-HTP; with little BH4, less 5-HTP forms Source 1, 7
• Iron — Metal in the active site of tryptophan hydroxylase; without iron this step stops Source 1In the ORY catalogue as a laboratory value: Eisen
• Oxygen — Tryptophan hydroxylase builds an oxygen atom into the ring of tryptophan; without it no 5-HTP Source 1
• Vitamin B6 — As pyridoxal phosphate, cofactor of AADC, which converts 5-HTP to serotonin; with little PLP, less serotonin forms Source 2In the ORY catalogue as a laboratory value: Vitamin B6
• Acetyl-CoA — Supplies AANAT with the acetyl group for N-acetylserotonin; the step that light slows Source 4
• S-adenosylmethionine (SAM) — Methyl group donor for ASMT, which forms melatonin; the last step to melatonin Source 4
• Vitamin B2 (FAD) — As FAD, cofactor of monoamine oxidase, which breaks down serotonin; this ends the serotonin signal Source 6

What acts on this pathway

• Inflammatory signals — Interferon-γ, TNF and bacterial LPS make many cells form more of the enzyme IDO. More tryptophan then enters the kynurenine pathway, and less remains for this step. Source 9, 5
• Competition at transport — Tryptophan shares the transporter LAT1 at the blood-brain barrier with other large neutral amino acids. How much reaches the brain depends on the ratio of these amino acids in the blood. Source 10
• Light at the eye — Light on the retina reports through the suprachiasmatic nucleus, the inner clock, and a nerve pathway to the pineal gland. Less of the enzyme AANAT is then formed, and the nightly rise of melatonin turns out smaller. Source 4

Sources

1. Roberts KM, Fitzpatrick PF. Mechanisms of tryptophan and tyrosine hydroxylase. IUBMB Life 2013 · PubMed 23441081
2. Paiardini A, Giardina G, Rossignoli G et al. New Insights Emerging from Recent Investigations on Human Group II Pyridoxal 5'-Phosphate Decarboxylases. Curr Med Chem 2017 · PubMed 27881066
3. Jones LA, Sun EW, Martin AM et al. The ever-changing roles of serotonin. Int J Biochem Cell Biol 2020 · PubMed 32479926
4. Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie 2015 · PubMed 25908646
5. Badawy AA. Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects. Int J Tryptophan Res 2017 · PubMed 28469468
6. Edmondson DE, Binda C. Monoamine Oxidases. Subcell Biochem 2018 · PubMed 29464559
7. Werner ER, Blau N, Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 2011 · PubMed 21867484
8. Agus A, Planchais J, Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe 2018 · PubMed 29902437
9. Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 2013 · PubMed 23103127
10. Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids 2013 · PubMed 22677921
11. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009 · PubMed 19630576

Whole pathway: Serotonin and melatonin

Related pathways

• Protein fermentation in the colon — tryptophan
• Kynurenine pathway — tryptophan
• NAD⁺ — tryptophan
• Carnitine — Eisen, Vitamin B6
• Dopamine, noradrenaline, adrenaline — Eisen, Vitamin B6

As of 2026-10-01. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending. Extended on 1 October 2026 with inflammation, transport, light, the indole route, the blood store, the melatonin receptors and now the 5-HT receptors and reuptake.
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