Melatonin

Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cows that could induce skin lightening in common frogs. This compound was later identified as a hormone secreted in the brain during the night, playing a crucial role in regulating the sleep-wake cycle, also known as the circadian rhythm, in vertebrates.

In vertebrates, melatonin's functions extend to synchronizing sleep-wake cycles, encompassing sleep-wake timing and blood pressure regulation, as well as controlling seasonal rhythmicity (circannual cycle), which includes reproduction, fattening, molting, and hibernation. Its effects are mediated through the activation of melatonin receptors and its role as an antioxidant. In plants and bacteria, it serves as a defense mechanism against oxidative stress, indicating its evolutionary significance. Mitochondria, key organelles, are the main producers of melatonin, underscoring its "ancient origins" and its fundamental role in protecting the earliest cells from reactive oxygen species.

In addition to its endogenous functions as a hormone and antioxidant, melatonin is also administered exogenously as a dietary supplement and medication. Melatonin is used medically primarily for sleep-related problems: for example, prolonged-release melatonin (Circadin) is approved in several countries for short-term treatment of insomnia in people aged 55 years of age or older. It is used in the treatment of sleep disorders, including insomnia and various circadian rhythm sleep disorders.

Biological activity

In humans, melatonin is presumed to act as a full agonist of two types of melatonin receptors: melatonin receptor 1, with picomolar binding affinity, and melatonin receptor 2, with nanomolar binding affinity. Both receptors are part of the G-protein coupled receptors (GPCRs) family, specifically the G_i/o alpha subunit GPCRs.

In vitro, melatonin functions as a high-capacity antioxidant or free radical scavenger within mitochondria, playing a dual role in combating cellular oxidative stress.

Biological functions

thumb|300px|class=skin-invert-image|Visible light entering the eye and the cascading positive and negative signalling pathways to neuronal structures in the mammalian brain that may follow: When the eyes are exposed to sunlight, the pineal gland's melatonin production is suppressed, resulting in the secretion of hormones that promote wakefulness. Conversely, in the absence of light, the pineal gland synthesizes melatonin unabated, leading to feelings of drowsiness and facilitating the onset of sleep.

Circadian rhythm

In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms. The establishment of regular melatonin levels in human infants occurs around the third month after birth, with peak concentrations observed between midnight and 8:00 am. It has been documented that melatonin production diminishes as a person ages. Additionally, a shift in the timing of melatonin secretion is observed during adolescence, resulting in delayed sleep and wake times, increasing their risk for delayed sleep phase disorder during this period. In adults, approximately 30 μg of melatonin is synthesized per day, nearly 80% of which occurs at night.

The antioxidant properties of melatonin were first recognized in 1993. In vitro studies reveal that melatonin directly neutralizes various reactive oxygen species, including hydroxyl (OH•), superoxide (O2−•), and reactive nitrogen species such as nitric oxide (NO•). In plants, melatonin works synergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant. The promotion of antioxidant enzyme expression, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, is mediated through melatonin receptor-triggered signal transduction pathways. An anti-inflammatory effect appears to be the most significant. thereby potentially mitigating acquired immunodeficiencies.

Weight regulation

Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect on leptin, a hormone that serves as a long-term indicator of the body's energy status.

Biochemistry

Biosynthesis

class=skin-invert-image|thumb|Melatonin biosynthesis

The biosynthesis of melatonin in animals involves a sequence of enzymatic reactions starting with <small>L</small>-tryptophan, which can be synthesized through the shikimate pathway from chorismate, found in plants, or obtained from protein catabolism. The initial step in the melatonin biosynthesis pathway is the hydroxylation of <small>L</small>-tryptophan's indole ring by the enzyme tryptophan hydroxylase, resulting in the formation of 5-hydroxytryptophan (5-HTP). Subsequently, 5-HTP undergoes decarboxylation, facilitated by pyridoxal phosphate and the enzyme 5-hydroxytryptophan decarboxylase, yielding serotonin.

Serotonin, an essential neurotransmitter, is further converted into N-acetylserotonin by the action of serotonin N-acetyltransferase, using acetyl-CoA. The final step in the pathway involves the methylation of N-acetylserotonin's hydroxyl group by hydroxyindole O-methyltransferase, with S-adenosyl methionine as the methyl donor, to produce melatonin.

Mechanism

class=skin-invert-image|thumb|Mechanism of melatonin biosynthesis

The mechanism of melatonin biosynthesis initiates with the hydroxylation of <small>L</small>-tryptophan, a process that requires the cofactor tetrahydrobiopterin (THB) to react with oxygen and the active site iron of tryptophan hydroxylase. Although the complete mechanism is not entirely understood, two main mechanisms have been proposed:

The first mechanism involves a slow transfer of one electron from THB to molecular oxygen (O₂), potentially producing a superoxide (). This superoxide could then recombine with the THB radical to form 4a-peroxypterin. 4a-peroxypterin may either react with the active site iron (II) to create an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron, facilitating the hydroxylation of <small>L</small>-tryptophan.

Alternatively, the second mechanism proposes that oxygen interacts with the active site iron (II) first, forming iron (III) superoxide. This molecule could then react with THB to form an iron-peroxypterin intermediate.

Following the formation of iron (IV) oxide from the iron-peroxypterin intermediate, this oxide selectively attacks a double bond to yield a carbocation at the C5 position of the indole ring. A subsequent 1,2-shift of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restore aromaticity, producing 5-hydroxy-<small>L</small>-tryptophan.

The decarboxylation of 5-hydroxy-<small>L</small>-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme with pyridoxal phosphate (PLP) as a cofactor. PLP forms an imine with the amino acid derivative, facilitating the breaking of the carbon–carbon bond and release of carbon dioxide. The protonation of the amine derived from tryptophan restores the aromaticity of the pyridine ring, leading to the production of 5-hydroxytryptamine and PLP.

Serotonin N-acetyltransferase, with histidine residue His122, is hypothesized to deprotonate the primary amine of 5-hydroxytryptamine. This deprotonation allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A then acts as a leaving group when attacked by a general base, producing N-acetylserotonin.

The final step in the biosynthesis of melatonin involves the methylation of N-acetylserotonin at the hydroxyl position by SAM, resulting in the production of S-adenosyl homocysteine (SAH) and melatonin.

Regulation

In vertebrates, the secretion of melatonin is regulated through the activation of the beta-1 adrenergic receptor by the hormone norepinephrine. Norepinephrine increases the concentration of intracellular cAMP via beta-adrenergic receptors, which in turn activates the cAMP-dependent protein kinase A (PKA). PKA then phosphorylates arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme in the melatonin synthesis pathway. When exposed to daylight, noradrenergic stimulation ceases, leading to the immediate degradation of the protein by proteasomal proteolysis.

Blue light, especially within the range, inhibits the biosynthesis of melatonin, with the degree of suppression being directly proportional to the intensity and duration of light exposure. Historically, humans in temperate climates experienced limited exposure to blue daylight during winter months, primarily receiving light from sources that emitted predominantly yellow light, such as fires. The incandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.<!-- Kayumov et al. showed that --> It has been found that light containing only wavelengths greater than 530&nbsp;nm does not suppress melatonin under bright-light conditions. The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression. Additionally, wearing blue-blocking goggles during the last hours before bedtime is recommended for individuals needing to adjust to an earlier bedtime since melatonin facilitates the onset of sleep.

Metabolism

Melatonin is metabolized with an elimination half-life ranging from 20 to 50 minutes. The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine as a waste product. It is primarily metabolized by the liver enzyme CYP1A2 and to a lesser extent by CYP1A1, CYP2C19, and CYP1B1.

Use as a medication and supplement

Insomnia

An extended-release pharmaceutical formulation of melatonin is approved under the brand name Circadin for the treatment of insomnia in certain settings, such as in people aged 55years of age or older. It is approved in the European Union, Israel, Australia, and countries in Asia and elsewhere in the world, but not in the United States (where it reached phase III clinical trials but was not approved). It recommended against fast-release or over-the-counter melatonin for treatment of insomnia.

Circadian rhythm sleep disorders

Melatonin may be useful in the treatment of delayed sleep phase syndrome.

Melatonin appears to have limited use against the sleep problems of people who work shift work. Tentative evidence suggests that it increases the length of time people are able to sleep. Some found that it was effective,

REM sleep behavior disorder

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies. However, clonazepam may be more effective. In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect. Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.

Available forms

thumb|300x300px|A bottle of melatonin tablets. Melatonin is also available in timed-release and in liquid forms.

A prolonged-release 2mg oral formulation of melatonin sold under the brand name Circadin is approved for use in the European Union in the short-term treatment of insomnia in people aged 55 years of age or older.

Melatonin is also available as an over-the-counter dietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by weight. Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or as a liquid. It is also available for use sublingually, or as transdermal patches. Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated. In 1917, Carey Pratt McCord and Floyd P. Allen found that feeding extracts from the pineal glands of cows caused the skin of tadpoles to lighten by contracting the dark epidermal melanophores.

The hormone melatonin was isolated in 1958 by Aaron B. Lerner, a dermatology professor, and his team at Yale University. Motivated by the possibility that a substance from the pineal gland could be beneficial in treating skin diseases, they extracted and identified melatonin from bovine pineal gland extracts. Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.

The first patent for the therapeutic use of melatonin as a low-dose sleep aid was awarded to Richard Wurtman at the Massachusetts Institute of Technology in 1995.

Etymology

The etymology of melatonin stems from its skin-lightening properties. As detailed in their publication in the Journal of the American Chemical Society, Lerner and his colleagues proposed the name melatonin, derived from the Greek words melas, meaning 'black' or 'dark', and tonos, meaning 'labour', 'colour' or 'suppress'. This naming convention follows that of serotonin, another agent affecting skin color, discovered in 1948 as a modulator of vascular tone, which influenced its name based on its serum vasoconstrictor effect. Melatonin was thus aptly named to reflect its role in preventing the darkening of the skin, highlighting the intersection of biochemistry and linguistics in scientific discovery.

located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei <!-- (SCN) --> from retinal photosensitive ganglion cells of the eyes rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.

In humans, ~30 μg of melatonin is produced daily and 80% of the total amount is produced in the night (W). The plasma maximum concentration of melatonin at night are 80–120 pg/mL and the concentrations during the day are between 10–20 pg/mL.

Many animals and humans use the variation in duration of melatonin production each day as a seasonal clock. In animals including humans, the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals. and hamsters. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone <!-- (LH) --> and follicle-stimulating hormone <!-- (FSH) --> from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin. In sheep, melatonin administration has also shown antioxidant and immune-modulatory regime in prenatally stressed offspring helping them survive the crucial first days of their lives.

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors. This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians. Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram. Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice. Studies conducted on lettuce grown in saline soil conditions have shown that the application of melatonin significantly mitigates the harmful effects of salinity. Foliar application increases the number of leaves, their surface area, increases fresh weight and the content of chlorophyll a and chlorophyll b, and the content of carotenoids compared to plants not treated with melatonin. Also acts as a growth inhibitor on fungal pathogens including Alternaria, Botrytis, and Fusarium spp. Decreases the speed of infection. As a seed treatment, protects Lupinus albus from fungi. Dramatically slows Pseudomonas syringae tomato DC3000 infecting Arabidopsis thaliana and infecting Nicotiana benthamiana. Danish pharmaceutical company Novo Nordisk have used genetically modified yeast (Saccharomyces cerevisiae) to produce melatonin.

Bacteria

Melatonin is produced by α-proteobacteria and photosynthetic cyanobacteria. There is no report of its occurrence in archaea which indicates that melatonin originated in bacteria

Archaea

In 2022, the discovery of serotonin N-acetyltransferase (SNAT)—the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway—in the archaeon Thermoplasma volcanium firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.

Food products

Naturally occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46&nbsp;ng/g, bananas, plums, grapes, rice, cereals, herbs, olive oil, wine, and beer. The consumption of milk and sour cherries may improve sleep quality. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.

References

External links

• Melatonin - Isomer Design