Melatonin Synthesis and Biochemistry

Synthesis of melatonin starts with L-tryptophan, an amino acid. The biochemical process is slightly different between plants and animals, since we are focused on the use of melatonin as a dietary supplement, we will cover the details that are pertinents to humans with some occasional references to other species. It is important to highlight that while we mostly associate melatonin with its sleep-related functions, this molecule has multiple functions inside the cells. Scientists believe that melatonin is produced inside the cells of all organisms such as fungi, bacteria, animals, and plants.

Figure #1 L-Tryptophan’s molecular structure:

For humans, L-tryptophan is an essential amino acid, meaning that we only obtain it through our diet; on the other hand, bacteria, fungi, and plants, can produce it from other substances. There are 4 steps involved in the synthesis of melatonin

1. L-Tryptophan first undergoes a process called hydroxylation using the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan
2. 5-hydroxytryptophan is decarboxylated by the enzyme aromatic amino acid decarboxylase to form serotonin
3. Serotonin is converted into N-acetylserotonin by the enzyme serotonin N-acetyltransferase 
4. N-acetylserotonin is finally converted into melatonin by Hydroxyindole O-methyltransferase and S-adenosyl methionine.

Figure #2 L-Serotonin’s molecular structure:

While we always associate melatonin with its sleep and circadian functions, it is important to know that this is not the only function of this important substance. Most of the melatonin that is produced by our body, is actually produced inside cells and never reaches the bloodstream. Melatonin is a potent antioxidant inside the cells. Plant cells tend to have higher levels of melatonin than animal cells (including us, humans). Scientists believe that such higher levels of melatonin that are observed in plants, are related to the limited ability that plants have to defend themselves from adverse environments. 

Most of the melatonin that circulates in our blood comes from the pineal gland (remember: the one inside the cells, does not reach the blood). In this post, we covered the biochemical steps that are involved in the synthesis of the melatonin molecule itself but this is a process that is highly regulated by light. Melatonin is normally released into the blood at night. When the retina is exposed to light, especially blue or green light, the production of melatonin in the pineal gland, is blocked. We will cover the relationship between light and melatonin production by the pineal gland in future posts. 

Figure #3 Melatonin’s molecular structure:

References:

• Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocyteS1. J Am Chem Soc. (1958) 80:2587. doi: 10.1021/ja01543a060

• Zhao D, Yu Y, Shen Y, Liu Q, Zhao Z, Sharma R and Reiter RJ (2019) Melatonin Synthesis and Function: Evolutionary History in Animals and Plants.Front. Endocrinol. 10:249. doi: 10.3389/fendo.2019.00249

• Reiter RJ, Tan DX, Rosales-Corral S, Manchester LC. The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini Rev Med Chem. 13:373–84. doi: 10.2174/138955713804999810

• Arnao MB, Hernández-Ruiz J. Growth conditions influence the melatonin content of tomato plants. Food Chem. (2013) 138:1212–4. doi: 10.1016/j.foodchem.2012.10.077