Melatonin Synthesis Pathway

Melatonin Synthesis

A flowchart showing the synthesis pathway of melatonin from dietary tryptophan. Enzyme names are shown above reaction arrows, and cofactors as well. Original Figure

Melatonin Synthesis: An Overview

Melatonin is synthesized using a four step pathway from it’s precursor: Tryptophan. Dietary tryptophan is absorbed into the bloodstream and circulated through the body. In the pineal gland, it is hydroxylated by TPOH to 5-hydroxy-Trp in the mitochondria, then decarboxylated by AADC in the pineal cytosol. This intermediate is called serotonin, another important neurotransmitter. There, serotonin can be used, can continue to either melatonin synthesis, or go through other metabolic pathways. For melatonin synthesis, 5-HT is acetylated on its free amine by AANAT, then O-methylated on the hydroxyl group by ASMT to form the final product of melatonin. (4)

The half life of melatonin is roughly 20 minutes in the bloodstream, so it is released immediately rather than stored. TPOH enzyme activity does increase at night, while the AAAD and HIOMT run continuously, however it is AANAT that is significantly regulated by circadian rhythms. This is in part because serotonin is a branch point for multiple other neurotransmitters synthetic pathways, and ASMT performs the O-methylation step for all of these as well. In rats, the concentration of melatonin increases by a factor of 10 in the pineal gland from day to night time, and by a factor of 5-10 in blood plasma. (4)


TPOH = Tryptophan-5-Hydroxylase

AADC = 5-Hydroxy-L-Tryptophan Decarboxylase (Aromatic Amino Acid Decarboxylase)

AANAT = Arylalkylamine-N-acetyltransferase

ASMT = Acetyl-serotonin O-methyltransferase

Click here for the chemical mechanism of the first enzyme in melatonin synthesis: TPOH

3 Responses to Melatonin Synthesis Pathway

  1. The figure is nicely complemented by the writing, which includes relevant and interesting information.

  2. As Roman said, your scheme and accompanying text is well-organized! However, since you make a point in the text to discuss the fact that serotonin is a branch point and can enter different pathways rather than continuing in melatonin synthesis, it would be helpful to indicate this in the scheme by labeling serotonin and including another set of arrows to show its other possible destinations.

  3. Henry Seidel says:

    I think this page wonderfully shows the synthesis of melatonin. My only comment would be to perhaps label the substrates in the pathways (melatonin, tryptophan etc.). That might make it slightly easier to follow along with the supplementing text.

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