Melatonin

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Melatonin (album)
.
This article is about melatonin as a hormone. For its role as a supplement and medication, see Melatonin as a medication and supplement.

Melatonin
Names
IUPAC name
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide
Other names
5-Methoxy-N-acetyltryptamine; N-Acetyl-5-methoxytryptamine; NSC-113928
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.000.725 Edit this at Wikidata
EC Number
  • 200-797-7200-797-7
KEGG
MeSH Melatonin
UNII
  • InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)
    Key: DRLFMBDRBRZALE-UHFFFAOYSA-N
  • CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC
Properties
C13H16N2O2
Molar mass 232.281 g/mol
Melting point 117
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Melatonin, an

vertebrates.[2][3]

In vertebrates, melatonin's functions extend to

organelles within cells, are the main producers of antioxidant melatonin,[9] underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells from reactive oxygen species.[10][11]

In addition to its

circadian rhythm sleep disorders
.

Biological activity

In humans, melatonin primarily acts as a potent

Gi/o alpha subunit GPCRs,[12][13] although melatonin receptor 1 also exhibits coupling with Gq alpha subunit.[12]

Furthermore, melatonin functions as a high-capacity

signal transduction pathways activated by the binding of melatonin to its receptors. Through these mechanisms, melatonin protects the cell against oxidative stress in two ways, and plays other roles in human health than only regulating the sleep-wake cycle.[14][12][15][16][17][18]

Biological functions

Visible light entering the eye and the cascading positive and negative signalling pathways to neuronal structures in the mamallian 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

Main article: Circadian rhythm

In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.

peak concentrations observed between midnight and 8:00 am.[20] It has been documented that melatonin production diminishes as a person ages.[21] 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.[22]

The antioxidant properties of melatonin were first recognized in 1993.

lipophilic antioxidant, in combating oxidative stress.[26] 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.[12][14]

Melatonin's concentration in the mitochondrial matrix is significantly higher than that found in the blood plasma,[15][16][17] emphasizing its role not only in direct free radical scavenging but also in modulating the expression of antioxidant enzymes and maintaining mitochondrial integrity. This multifaceted role shows the physiological significance of melatonin as a mitochondrial antioxidant, a notion supported by numerous scholars.[14][15][16][17][18]

Furthermore, the interaction of melatonin with reactive oxygen and nitrogen species results in the formation of metabolites capable of reducing free radicals.

redox reactions with free radicals.[12][18]

Immune system

Melatonin's interaction with the

acquired immunodeficiencies.[30]

Weight regulation

Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect on

leptin resistance
.

Biochemistry

Biosynthesis

Melatonin biosynthesis

The

5-hydroxytryptophan decarboxylase, yielding serotonin.[33]

Serotonin, an essential

methyl donor, to produce melatonin.[34]

In

photosynthetic cells, additionally involves carbon dioxide. While the subsequent biosynthetic reactions share similarities with those in animals, there are slight variations in the enzymes involved in the final stages.[35][36]

The hypothesis that melatonin synthesis occurs within mitochondria and

domains of life.[37]

Mechanism

Mechanism of melatonin biosynthesis

The mechanism of melatonin biosynthesis initiates with the hydroxylation of L-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 (O−2). 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 L-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

1,2-shift of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restore aromaticity, producing 5-hydroxy-L-tryptophan.[38]

The decarboxylation of 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme with

pyridine ring, leading to the production of 5-hydroxytryptamine and PLP.[40]

Serotonin N-acetyltransferase, with

tetrahedral intermediate. The thiol from coenzyme A then acts as a leaving group when attacked by a general base, producing N-acetylserotonin.[41]

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.[40][42]

Regulation

In vertebrates, the secretion of melatonin is regulated through the activation of the

dim-light melatonin onset
.

Blue light, especially within the 460–480 

incandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.[47] It has been found that light containing only wavelengths greater than 530 nm does not suppress melatonin under bright-light conditions.[48] The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.[49] 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.[50]

Metabolism

Melatonin is

elimination half-life ranging from 20 to 50 minutes.[51][2][52] The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine as a waste product.[53]

Measurement

For both research and clinical purposes, melatonin levels in humans can be determined through saliva or blood plasma analysis.[54]

Use as a medication and supplement

Main article: Melatonin as a medication and supplement

Melatonin is used both as a

melatonin receptor agonists, namely ramelteon, tasimelteon, and agomelatine, are used in medicine.[56][57]

A study published by the

pharmacy compounding practices. A preceding study from 2022 concluded that consuming unregulated melatonin products can expose individuals, including children, to melatonin quantities ranging from 40 to 130 times higher than the recommended levels when products are used 'as directed'.[58]

History

Main article: History of the pineal gland

Discovery

Melatonin's discovery is linked to the study of skin color changes in some amphibians and reptiles, a phenomenon initially observed through the administration of pineal gland extracts.

melanophores.[61][62]

The hormone melatonin was isolated in 1958 by

skin diseases, they extracted and identified melatonin from bovine pineal gland extracts.[63] Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.[64]

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.[65]

Etymology

The etymology of melatonin stems from its skin-lightening properties. As detailed in their publication in the

vasoconstrictor effect.[70] 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.[66]

Occurrence

Animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[71] located in the center of the brain but outside the

nocturnal (night-active) animals and sleep in diurnal ones including humans.[74]

Many animals use the variation in duration of melatonin production each day as a seasonal clock.

short-day breeders
is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering its levels.

brain hemisphere at a time). Similar trends have been found in sirenians.[79]

Plants

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions.[8][80] 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.[36][81] 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.[8] In some common foods and beverages, including coffee[8] and walnuts,[82] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

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.[36][83][84]

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.[85][86]

Fungal disease resistance is another role. Added melatonin increases

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.[87]

Fungi

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.[88] Danish pharmaceutical company Novo Nordisk have used genetically modified yeast (Saccharomyces cerevisiae) to produce melatonin.[89]

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[11] most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.[10]

Novo Nordisk have used genetically modified Escherichia coli to produce melatonin.[90][91]

Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,[92] bananas, plums, grapes, rice, cereals, herbs,[93] olive oil, wine,[94] and beer.[95] The consumption of milk and sour cherries may improve sleep quality.[96] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[97] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.[98]

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External links

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