Melatonin, also called N-acetyl-5-methoxytryptamine, was first discovered by Aaron Lerner in 1958. He found it in the pineal glands of cows. Melatonin is the main hormone made by the pineal gland and plays an important role in the body. While most melatonin is produced in the pineal gland, it is also made in other parts of the body, such as the retina (in the eye), bone marrow cells, platelets, skin, immune cells, the Harderian gland, and the cerebellum (part of the brain). The digestive system, especially in animals with backbones, also produces a large amount of melatonin. One of melatonin's most important jobs is to help control the body's sleep and wake cycle.
Functions of Melatonin
Melatonin has many important roles in the body. First, it can slow down the hypothalamic-pituitary-gonadal (HPG) axis by lowering the levels of certain hormones like gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). It also works directly on the reproductive organs to reduce hormones such as androgens, estrogens, and progestogens. Second, melatonin helps control the nervous and immune systems, and it is a strong antioxidant that removes harmful free radicals, which helps keep the body healthy. Finally, melatonin is broken down in the liver. If the liver is damaged, this process can be affected, causing changes in melatonin levels in the body.
How Melatonin Is Synthesized and Secreted
Synthesis Pathway and Key Enzymes
The nervous system controls how melatonin is made. It starts in a part of the brain called the paraventricular nucleus in the hypothalamus. This area sends signals directly or indirectly to nerve cells in the spinal cord at the T1 level. These nerve cells then connect to the superior cervical ganglion, a group of nerve cells outside the spinal cord. From there, nerves reach the pineal gland and control melatonin production.
Figure 1. Neuroanatomical pathway of light stimulus to the pineal gland. (Vasey, C. et al. 2021)
The synthesis of melatonin is a complex biochemical process that occurs primarily in the pineal gland of mammals. It begins with the amino acid tryptophan and proceeds through a series of enzymatic reactions to produce melatonin. The detailed synthesis process is as follows:
Tryptophan Hydroxylation: Tryptophan (Trp) is converted into 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase (TPH).Decarboxylation: 5-HTP is then decarboxylated by L-aromatic amino acid decarboxylase (AAAD) to form 5-hydroxytryptamine (5-HT), also known as serotonin.Acetylation: Serotonin is acetylated by arylalkylamine N-acetyltransferase (AANAT or SNAT) using acetyl-CoA as a co-substrate, yielding N-acetyl-5-hydroxytryptamine (N-acetyl-5-HT).Methylation: Finally, N-acetyl-5-HT is methylated by N-acetylserotonin O-methyltransferase (ASMT or HIOMT) to produce melatonin.
Figure 2. The metabolic pathways of melatonin.
Beyond mammalian systems, both plant species and microbial organisms possess the ability to produce melatonin endogenously. While plant melatonin biosynthetic pathways share fundamental similarities with animal systems, they demonstrate increased complexity through diverse intermediary metabolites and enzymatic reactions. The process initiates with tryptophan conversion to tryptamine, followed by hydroxylation to form 5-hydroxytryptamine (serotonin). This precursor molecule then undergoes sequential acetylation and methylation to generate the final melatonin product.
Commercial melatonin manufacturing utilizes synthetic chemical approaches for large-scale production. A representative synthetic methodology begins with 4-bromo-1-chlorobutane as the starting material, which undergoes transformation to 4-chlorobutylbenzamide. The process continues through halogen substitution using sodium iodide, incorporation of ethyl acetoacetate functionality, and concludes with hydrolysis and deprotection steps to obtain melatonin. Beyond traditional synthetic methodologies, innovative techniques including inverse aqueous phase catalysis and microwave-enhanced synthesis have emerged as promising alternative production strategies.
Main Metabolites of Melatonin and Their Roles
| Metabolite | Formation Pathway | Notes / Biological Significance |
|---|---|---|
| 6-Hydroxymelatonin (6-OH-Mel) | Formed through CYP1A2-mediated hydroxylation of melatonin. | Rapidly conjugated with sulfate or glucuronic acid to increase solubility and facilitate excretion. |
| 6-Sulfatoxymelatonin (aMT6s) | Produced via sulfation of 6-OH-Mel by SULT1A1 enzyme. | Major urinary metabolite of melatonin; accounts for >80% of excretion. Serves as a non-invasive biomarker. |
| N-Acetylserotonin (NAS) | Precursor formed when serotonin is acetylated by AANAT. | Bioactive molecule with neuroprotective and circadian roles. Accumulates if HIOMT is impaired. |
| Other Minor Metabolites | Include 5-methoxytryptamine, AFMK, and AMK via non-enzymatic or oxidative degradation. | Involved in antioxidant pathways and oxidative stress response; useful in melatonin degradation studies. |
Circadian Rhythm of Melatonin Secretion
Melatonin secretion exhibits a distinct circadian rhythm. Light signals are transmitted from the retina to the pineal gland via the suprachiasmatic nucleus (SCN) of the hypothalamus. In humans, melatonin secretion typically begins shortly after sunset, peaks between 2:00 a.m. and 4:00 a.m., and gradually declines during the latter half of the night. Approximately 80% of melatonin is synthesized during nighttime, with serum concentrations ranging from 80 to 120 pg/mL. During the daytime, melatonin levels drop significantly, with serum concentrations falling to 10–20 pg/mL.
Factors Influencing Melatonin Secretion
Light Exposure:
Blue light significantly suppresses melatonin secretion. It activates photoreceptors in the retina, which, through neural pathways, inhibit the synthesis and release of melatonin by the pineal gland, thereby promoting wakefulness.
Diet:
Tryptophan, the precursor of melatonin, plays a key role in its synthesis. Consuming tryptophan-rich foods, such as milk and bananas, can increase the availability of this amino acid, providing sufficient substrate for melatonin biosynthesis and thereby enhancing its secretion.
Medications:
Certain drugs, such as β-adrenergic blockers and antidepressants, can alter melatonin secretion. β-blockers inhibit melatonin synthesis by blocking associated signaling pathways. Antidepressants may indirectly affect melatonin levels by altering the balance of neurotransmitters in the brain.
Other Factors:
Nonspecific influences such as stress and physical activity can also impact melatonin production. Chronic stress disrupts the endocrine system and suppresses melatonin secretion. Conversely, moderate exercise may promote melatonin production, while excessive or intense exercise could lead to dysregulation of its secretion.
The Relationship Between Melatonin and Sleep Disorders
Melatonin plays a vital role in regulating the sleep-wake cycle. Under natural conditions, the brain secretes little to no melatonin during the day. However, as evening approaches, melatonin secretion gradually increases—rising rapidly around 9:00 p.m., signaling the brain to initiate sleep and transition into a sleep state. By inducing natural sleep, melatonin helps to alleviate sleep disorders and improve sleep quality.
Abnormal melatonin metabolism is commonly observed in individuals with sleep disorders, with enzyme deficiencies being a key contributing factor. One typical example is reduced activity of arylalkylamine N-acetyltransferase (AANAT), an essential enzyme in melatonin synthesis that converts serotonin (5-HT) into N-acetyl-5-hydroxytryptamine. When the activity of AANAT is impaired, this critical intermediate step is hindered, resulting in reduced melatonin production and consequently lower circulating melatonin levels, which can disrupt normal sleep patterns.
Dysfunction of hydroxyindole-O-methyltransferase (HIOMT or ASMT), another crucial enzyme, also significantly impacts melatonin biosynthesis. This enzyme catalyzes the conversion of N-acetyl-5-HT to melatonin. If HIOMT function is compromised, the final step in melatonin synthesis is affected, leading to a drop in endogenous melatonin levels.
Furthermore, the metabolic rate of exogenous melatonin exhibits interindividual variability, which is closely related to the CYP1A2 genotype. Different CYP1A2 genetic variants affect hepatic enzyme activity, resulting in varying rates of melatonin metabolism. Rapid metabolism shortens the duration of action of exogenous melatonin, reducing its effectiveness in regulating sleep. Conversely, slow metabolism may lead to elevated melatonin concentrations in the body, potentially causing adverse effects. These metabolic abnormalities, and their impact on melatonin levels, are closely linked and collectively influence sleep quality.
Melatonin as an Adjunctive Treatment for Sleep Disorders
Melatonin is generally effective in treating insomnia, provided it is used under medical supervision. It not only helps regulate sleep-wake cycles but also promotes emotional relaxation, reduces nighttime awakenings, and facilitates sleep onset. Therefore, melatonin has certain adjunctive therapeutic benefits for sleep disorders. Its efficacy is greatest when taken before bedtime, as melatonin production and release from the pineal gland are naturally elevated in response to darkness—thereby encouraging the body to transition into a sleep state.
Conclusion
The hormone melatonin serves as a crucial regulator of circadian rhythms and sleep patterns in humans. This complex molecule is produced mainly within the pineal gland via precisely controlled enzymatic processes. Environmental light exposure, nutritional intake, and stress levels significantly influence its circadian production patterns. Following synthesis, melatonin undergoes metabolic transformation into bioactive compounds that facilitate sleep regulation while providing cellular protection from oxidative damage.
When melatonin production or breakdown becomes impaired—whether through enzymatic dysfunction, hereditary variations, or environmental disruptions—individuals may experience sleep disorders and disrupted circadian timing. These metabolic and control mechanisms provide valuable insights into sleep's biological foundations and validate melatonin's therapeutic potential as a safe adjunctive intervention for sleep-related disorders.
Continued investigation into melatonin's biosynthetic pathways, metabolic processes, and clinical applications will further advance our capacity to address sleep disturbances and promote optimal health outcomes.
References
- Vasey, C., McBride, J., & Penta, K. (2021). Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients, 13(10), 3480. https://doi.org/10.3390/nu13103480
- Bocheva, G., Bakalov, D., Iliev, P., & Tafradjiiska-Hadjiolova, R. (2024). The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging. International journal of molecular sciences, 25(10), 5122. https://doi.org/10.3390/ijms25105122
- Zisapel N. (2018). New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. British journal of pharmacology, 175(16), 3190–3199. https://doi.org/10.1111/bph.14116
