Serotonin - Metabolism
Serotonin or 5-hydroxytryptamine is synthesized from L-tryptophan. The quantity of tryptophan ingested daily is about 0.5 to 1g; the recommended daily allowance is about 200 mg, of which only a small part is converted into serotonin.
Indeed, in addition to the metabolic pathway leading to serotonin, tryptophan is used in protein synthesis and it is transformed by hepatic tryptophan pyrrolase, generally called tryptophan 2-3-dioxygenase and by indolaleamine-2,3-dioxygenase, into N-formylkynurenine then into kynurenine, precursor of xanthurenic acid and nicotinic acid. Activity of tryptophan pyrrolase is increased by cortisol, ethanol consumption and tryptophan intake. The activity of indoleamine-2,3-dioxygenase increases during stimulation of the immune system. The activation of these 2 enzymes of the kynurenine pathway could reduce the amount of tryptophan available for serotonin biosynthesis.
Tryptophan: main metabolic pathways
Transformation of tryptophan into serotonin involves two steps:
- Hydroxylation in 5-hydroxytryptophan catalyzed by tryptophan hydroxylase, which is the rate limiting enzyme of the synthesis. This enzyme requires for its activity the presence of tetrahydrobiopterine, oxygen, NADPH2 and a metal, iron or copper.
- Decarboxylation of 5-hydroxytryptophan is catalyzed by L-aromatic amino acid decarboxylase with pyridoxal-phosphate as coenzyme.
In the brain, serotonin biosynthesis depends on the quantity of tryptophan which crosses the blood-brain barrier. Only free plasma tryptophan, i.e. unbound to albumin, penetrates into the brain; decrease of its free ratio reduces its penetration. Moreover, other amino acids are in competition with free tryptophan and limit its entry in the brain. Plasma cortisol, whose level is increased in depressed patients, decreases free L-tyrosine and free L-tryptophan concentrations in plasma, i.e. the forms which penetrate into the brain. Insulin, of which secretion is increased by carbohydrates, has an opposite effect and decreases the concentration of the amino acids other than tryptophan.
Biosynthesis of serotonin and melatonin
Transformation of serotonin into melatonin, which should not be regarded as a degradation pathway because melatonin is also active, is carried out primarily in the pineal gland. It involves two steps:
- Acetylation of the amine group by N-acetyl transferase leading to N-acetyl-serotonin.
- Methylation of the OH group by 5- hydroxyindole-O-methyltransferase catalyzing the transfer of a methyl group from S-adenosyl-methionine to obtain acetyl-5-methoxytryptamine or melatonin.
The concentration of melatonin in the pineal gland presents circadian variations: it follows the variations of N-acetyl transferase activity, increasing during the night and decreasing during the day, darkness and light playing a regulatory role via catecholamines. Light inhibits melatonin biosynthesis.
Serotonin is found in many tissues:
- In the digestive tract which contains about 95% of the total amount of serotonin of the body, localized in enterochromaffin cells.
- in the central nervous system of all species: higher concentrations are found in brainstem than in cortex. Serotonin, released by presynaptic serotonergic neurons in synaptic clefts, activates specific receptors and is partly reuptaken by presynaptic neurons.
- in platelets: practically all blood serotonin (concentration going from 100 to 200 micrograms per liter) is found in platelets which do not synthesize it, but take it from plasma where it is released by enterochromaffin cells. The uptake of serotonin by platelets is very fast. The half-life of serotonin in platelets is the same as that of platelets, i.e. five or six days. Serotonin released from platelets in plasma has a relatively localized effect on the vessels where it is released, for example during migraine.
The half-life of serotonin is long in platelets and intestine, and very short, a few minutes, in the brain. The concentration of a compound in an organ, static view of a dynamic phenomenon, is not necessarily a good representation of metabolic activity and turn-over.
Melatonin found in plasma is released from the pineal gland. Its plasma concentration decreases during ageing.
Serotonin is converted into inactive molecules by biotransformations:
- Oxydative deamination of the lateral amino chain by monoamine oxidase, leading to 5-hydroxy-indol-acetaldehyde which is then oxidized into 5-hydroxy-indol-acetic acid (5-HIAA) found in urines in quantities normally lower than 10 mg/24 h.
- Conjugation by glucuronic acid or sulfate of the hydroxyl group OH in 5-position .
Main pathway of serotonin catabolism