COMT-Genetik (Catechol-O-Methyltransferase): the pathway in the body

COMT-Genetik (Catechol-O-Methyltransferase) is part of the pathway “Dopamine, noradrenaline, adrenaline”. This page shows the whole pathway; the station of COMT-Genetik (Catechol-O-Methyltransferase) is highlighted.

Where this laboratory value sits: COMT — enzyme, gene with Val158Met. Catechol-O-methyltransferase attaches a methyl group from SAM to dopamine, noradrenaline, adrenaline and their breakdown stages. In the COMT gene, the Val158Met variant is studied most; its Met form is less stable at body temperature. Source 7, 10

In brief

Dopamine, noradrenaline and adrenaline are catecholamines formed from the amino acids phenylalanine and tyrosine. They carry signals in the nervous system; adrenaline also acts as a hormone from the adrenal medulla. They act on heart, vessels and blood sugar.

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. Phenylalanine → Tyrosine PAH · BH4, Iron Phenylalanine hydroxylase (PAH) attaches an OH group to phenylalanine, forming tyrosine. The enzyme needs iron and the cofactor tetrahydrobiopterin (BH4). Its pool feeds the next, slowest step. Source 2, 3, 1↑ supplies Tyrosine is the substrate of tyrosine hydroxylase. Because this step sets the pace, it is usually the enzyme, not the tyrosine pool, that decides how much catecholamine forms. established physiology Source 1
   ⚖ When the balance tips

   too much — More tyrosine does not bring unlimited dopamine: tyrosine hydroxylase is usually already saturated with tyrosine, and in laboratory experiments high amounts of tyrosine even inhibit the enzyme.

   too little — If little tyrosine is present and PAH also works slowly, tyrosine hydroxylase receives less substrate; the first step towards the catecholamines slows down.

   observed in studies · Source 1, 2

2. Tyrosine → L-DOPA Tyrosine hydroxylase · BH4, Iron Tyrosine hydroxylase turns tyrosine into L-DOPA; it too needs iron and BH4. This is the slowest step of the pathway – here the cell regulates how much is formed. Dopamine and noradrenaline slow this step by feedback. Source 1, 3↑ supplies Tyrosine hydroxylase is the control point of the pathway: dopamine and noradrenaline slow it by feedback, and phosphorylation during nerve activity releases the brake. AADC usually processes L-DOPA further at once. established physiology Source 1, 3
   ⚖ When the balance tips

   too much — If more L-DOPA forms, AADC rapidly converts it into dopamine; the enzyme is widespread in the body and also works outside the brain, as the Carbidopa product information describes.

   too little — If little BH4 or iron is present, tyrosine hydroxylase cannot keep pace; less L-DOPA then forms, and in turn less dopamine, noradrenaline and adrenaline.

   established physiology · Source 1, 3, 4, 8

3. L-DOPA → Dopamine AADC · Vitamin B6 (PLP) The enzyme AADC (decarboxylase) removes a carboxyl group from L-DOPA, forming dopamine. It needs pyridoxal phosphate, the active form of vitamin B6. It acts as a messenger and is also the precursor of noradrenaline. Source 4, 1↕ both, depending on amount Dopamine is messenger and precursor at once: stored in vesicles, it is released or converted into noradrenaline. At the same time it slows tyrosine hydroxylase, and so its own formation. established physiology Source 1, 7
   ⚖ When the balance tips

   too much — If dopamine builds up in the cell outside the vesicles, MAO breaks it down, producing a reactive aldehyde and hydrogen peroxide. At the same time, more dopamine inhibits tyrosine hydroxylase more strongly.

   too little — If little dopamine forms, its brake on tyrosine hydroxylase weakens, and less precursor is available for noradrenaline.

   established physiology · Source 7, 1

4. Dopamine → Noradrenaline Dopamine β-hydroxylase · Vitamin C, Copper In storage vesicles, dopamine β-hydroxylase attaches an OH group to dopamine. This copper-containing enzyme uses vitamin C (ascorbate) as an electron donor. It makes the heart beat more strongly and narrows blood vessels. Source 1, 5↑ supplies Noradrenaline is the messenger of the sympathetic nerves: at adrenoceptors of the heart and blood vessels it makes the heart beat more strongly and narrows vessels. The nerve cells reabsorb most of it. established physiology Source 7
   ⚖ When the balance tips

   too much — If much noradrenaline is released, the nerve cells reabsorb most of it and break it down via MAO to DHPG; what passes into the blood amplifies the action on heart and vessels.

   too little — If little vitamin C or copper is present, dopamine β-hydroxylase works more slowly; more dopamine then remains in the vesicles, and less noradrenaline is available.

   established physiology · Source 7, 5, 1

5. Noradrenaline → Adrenaline PNMT · SAM In the adrenal medulla, PNMT transfers a methyl group from SAM (S-adenosylmethionine) to noradrenaline. The formation of this enzyme is regulated mainly by cortisol. In the blood it speeds up the heartbeat and raises blood sugar. Source 6, 1↑ supplies Adrenaline passes from the adrenal medulla into the blood and acts as a stress hormone: it speeds up the heartbeat, releases glucose from the liver's glycogen stores and so raises blood sugar. established physiology Source 6, 7
   ⚖ When the balance tips

   too much — If much adrenaline is released, the heart beats faster and blood sugar rises; COMT in the adrenal medulla converts part of it to metanephrine even before release.

   too little — If little SAM is present, or little cortisol, which drives formation of PNMT, less adrenaline forms; more noradrenaline then leaves the adrenal medulla unchanged.

   established physiology · Source 6, 7

6. DOPAC → Homovanillic acid COMT · SAM The enzyme COMT (catechol-O-methyltransferase) attaches a methyl group to DOPAC. This forms homovanillic acid, which is excreted in urine. This ends dopamine's action. Source 7↓ depletes Homovanillic acid is the end product of dopamine breakdown and no longer acts as a messenger. With its formation, dopamine finally leaves the cycle and is excreted via the kidneys. established physiology Source 7
   ⚖ When the balance tips

   too much — If more dopamine is formed and broken down, more homovanillic acid forms; its amount follows turnover, not the amount of dopamine acting at that moment.

   too little — If COMT is slowed or little SAM is present, more DOPAC is left over and less homovanillic acid forms.

   established physiology · Source 7, 9

7. DHPG → MHPG COMT · SAM Outside the nerve cells, COMT attaches a methyl group to DHPG. This forms MHPG. It no longer acts as a messenger. Source 7↓ depletes MHPG is an intermediate with no messenger action. It passes into the blood and is mostly processed further to vanillylmandelic acid in the liver. established physiology Source 7
   ⚖ When the balance tips

   too much — If more noradrenaline is broken down, more MHPG forms, and more vanillylmandelic acid arises in the liver.

   too little — If COMT is slowed or little SAM is present, more DHPG is left over and less MHPG forms.

   established physiology · Source 7, 9

8. MHPG → Vanillylmandelic acid ADH, ALDH · NAD⁺ In the liver, alcohol and aldehyde dehydrogenases convert MHPG into vanillylmandelic acid. The metanephrines also lead into this substance via MAO. Through it the catecholamines leave the body. Source 7↓ depletes Vanillylmandelic acid is the end product of noradrenaline and adrenaline and no longer acts as a messenger. Through it the catecholamines leave the body in the urine. established physiology Source 7
   ⚖ When the balance tips

   too much — If more noradrenaline and adrenaline are turned over, more vanillylmandelic acid forms; its amount follows total turnover, not the amount acting at that moment.

   too little — If the liver's dehydrogenases work more slowly or little NAD⁺ is present, less vanillylmandelic acid forms and more MHPG remains unchanged.

   established physiology · Source 7

9. Metanephrines → Vanillylmandelic acid MAO In the liver, alcohol and aldehyde dehydrogenases convert MHPG into vanillylmandelic acid. The metanephrines also lead into this substance via MAO. Through it the catecholamines leave the body. Source 7↓ depletes Vanillylmandelic acid is the end product of noradrenaline and adrenaline and no longer acts as a messenger. Through it the catecholamines leave the body in the urine. established physiology Source 7
   ⚖ When the balance tips

   too much — If more noradrenaline and adrenaline are turned over, more vanillylmandelic acid forms; its amount follows total turnover, not the amount acting at that moment.

   too little — If the liver's dehydrogenases work more slowly or little NAD⁺ is present, less vanillylmandelic acid forms and more MHPG remains unchanged.

   established physiology · Source 7

Further stations

• Phenylalanine — amino acid Phenylalanine is an amino acid that the body cannot make itself. It comes from dietary protein and from the breakdown of the body's own proteins. It is the starting material for all catecholamines. Source 2↑ supplies Phenylalanine is the starting material of the pathway: PAH converts it into tyrosine. What is not built into protein flows this way into tyrosine formation and on to the catecholamines. established physiology Source 2
  ⚖ When the balance tips

  too much — If phenylalanine builds up because PAH cannot keep pace, more of it stays in the blood, and less tyrosine forms along this route.

  too little — If little phenylalanine arrives, tyrosine comes mainly straight from dietary protein; the route to the catecholamines then starts one step later.

  established physiology · Source 2

• DOPAC — dihydroxyphenylacetic acid Dopamine that is not stored in vesicles is broken down inside the cell by the enzyme MAO (monoamine oxidase). DOPAC forms via an aldehyde intermediate. In this way MAO removes free dopamine from the cell. Source 7↓ depletes MAO breakdown removes dopamine that has not reached the vesicles from the cell. DOPAC itself does not act as a messenger; its amount mainly reflects turnover inside the cell. established physiology Source 7
  ⚖ When the balance tips

  too much — If MAO breakdown runs harder, because more dopamine leaks from the vesicles or more is formed, more DOPAC forms and less dopamine remains available.

  too little — If MAO is slowed, for example by MAO inhibitors, less DOPAC forms; more dopamine remains in the cell and is stored in vesicles to a greater extent or broken down by other routes.

  established physiology · Source 7

• DHPG — dihydroxyphenylglycol Most noradrenaline is broken down within the nerve cells themselves: MAO turns it into an aldehyde, which is further converted to DHPG. This ends the action of this noradrenaline. Source 7↓ depletes With DHPG, noradrenaline leaves the nerve cell as an inactive breakdown product. Because most of it seeps out of storage vesicles or returns by reuptake, DHPG mainly reflects turnover inside the cell. established physiology Source 7
  ⚖ When the balance tips

  too much — If more noradrenaline leaks from the vesicles or more is taken back up, MAO breaks more down to DHPG; less noradrenaline is then available for release.

  too little — If MAO is slowed, less DHPG forms; more noradrenaline remains in the nerve cell and is stored back into vesicles.

  established physiology · Source 7

• Metanephrines — normetanephrine, metanephrine Mainly in the adrenal medulla, COMT methylates noradrenaline and adrenaline directly. This forms normetanephrine and metanephrine – a quantitatively smaller breakdown route. This too ends the hormones' action. Source 7↓ depletes Direct methylation by COMT removes the receptor action of noradrenaline and adrenaline. Because it already takes place in the cells of the adrenal medulla, metanephrines form continuously, even without release. established physiology Source 7
  ⚖ When the balance tips

  too much — If the adrenal medulla forms more noradrenaline and adrenaline, more of it leaks from the vesicles and COMT makes more metanephrines from it, even when no more is released.

  too little — If COMT is slowed or little SAM is present, fewer metanephrines form; noradrenaline and adrenaline then remain unchanged for longer.

  established physiology · Source 7, 9

• COMT — enzyme, gene with Val158Met Catechol-O-methyltransferase attaches a methyl group from SAM to dopamine, noradrenaline, adrenaline and their breakdown stages. In the COMT gene, the Val158Met variant is studied most; its Met form is less stable at body temperature. Source 7, 10↓ depletes COMT inactivates catecholamines by methylation. In the prefrontal cortex, where there are few dopamine transporters, COMT has a particularly large say in how long dopamine acts there. observed in studies Source 10, 11
  ⚖ When the balance tips

  too much — If COMT works faster, as with the Val form, dopamine in the prefrontal cortex is methylated more quickly, and less of it remains active between the nerve cells.

  too little — With the Met form, enzyme activity in brain tissue was lower; dopamine in the prefrontal cortex is then broken down more slowly and acts there for longer.

  observed in studies · Source 10, 11

  Field of research — The Val158Met variant is studied in research on memory, attention and stress processing; the results are inconsistent. Source 11

Cofactors in this pathway

• Tetrahydrobiopterin (BH4) — Cofactor of phenylalanine and tyrosine hydroxylase when oxygen is inserted; without BH4 no L-DOPA Source 3
• Iron — Sits in the active site of phenylalanine and tyrosine hydroxylase; without iron both steps stop Source 1, 2In the ORY catalogue as a laboratory value: Eisen
• Vitamin B6 — As pyridoxal phosphate, cofactor of AADC, which converts L-DOPA into dopamine; with little PLP, less dopamine forms Source 4In the ORY catalogue as a laboratory value: Vitamin B6
• Copper — Metal at the centre of dopamine β-hydroxylase, which converts dopamine into noradrenaline; no copper, no noradrenaline Source 5In the ORY catalogue as a laboratory value: Kupfer (Cu)
• Vitamin C — Electron donor of dopamine β-hydroxylase inside the storage vesicle; with little of it, less noradrenaline forms Source 5In the ORY catalogue as a laboratory value: Vitamin C (Ascorbinsäure)
• SAM (from methionine) — Methyl group donor of PNMT and of COMT; without SAM no adrenaline and no metanephrine Source 6, 7In the ORY catalogue as a laboratory value: Methionin
• Magnesium — Ion in the active site of COMT when catecholamines are converted; COMT needs it to methylate Source 9In the ORY catalogue as a laboratory value: Magnesium
• NAD⁺ — Accepts hydrogen at the aldehyde dehydrogenases of the breakdown route; this forms vanillylmandelic acid Source 7In the ORY catalogue as a laboratory value: NAD⁺ (Nicotinamidadenindinukleotid)

What acts on this pathway

• Carbidopa — Carbidopa inhibits the decarboxylase outside the brain, so less L-DOPA is converted to dopamine there. Carbidopa does not enter the brain. The product information describes this mechanism. Source 8

Sources

1. Daubner SC, Le T, Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 2011 · PubMed 21176768
2. Flydal MI, Martinez A. Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life 2013 · PubMed 23457044
3. Werner ER, Blau N, Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 2011 · PubMed 21867484
4. 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
5. Prigge ST, Mains RE, Eipper BA et al. New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci 2000 · PubMed 11028916
6. Wong DL. Epinephrine biosynthesis: hormonal and neural control during stress. Cell Mol Neurobiol 2006 · PubMed 16645894
7. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 2004 · PubMed 15317907
8. US prescribing information Sinemet (Carbidopa/Levodopa, DailyMed), section Clinical Pharmacology, Pharmacodynamics · Prescribing information
9. Ma Z, Liu H, Wu B. Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders. Br J Clin Pharmacol 2014 · PubMed 23713800
10. Chen J, Lipska BK, Halim N et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004 · PubMed 15457404
11. Witte AV, Flöel A. Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2012 · PubMed 22138198

Whole pathway: Dopamine, noradrenaline, adrenaline

Related pathways

• Vitamin B6 — l-dopa
• Protein fermentation in the colon — tyrosine
• Carnitine — Eisen, Vitamin B6
• Estradiol — Eisen, Methionin
• Oestrogen breakdown — Eisen, Methionin

As of 2026-09-16. Draft, written by Claude to schema v2; sources checked in PubMed; expert approval pending
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