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Melatonin

Topic: Chemistry

 From HandWiki - Reading time: 21 min
Short description: Hormone released by the pineal gland
Not to be confused with melanin. For the album, see Melatonin (album).
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
EC Number
  • 200-797-7
KEGG
Properties
C13H16N2O2
Molar mass 232.281 g/mol
Melting point 117 °C
Pharmacology
Pharmacokinetics:
20–50 minutes[1][2][3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Melatonin is a natural compound, specifically an indoleamine, produced by and found in different organisms including bacteria and eukaryotes.[4] It was discovered by Aaron B. Lerner and colleagues in 1958 as a substance of the pineal gland from cows that could induce skin lightening in common frogs. It was subsequently discovered as a hormone released in the brain at night which controls the sleep–wake cycle in vertebrates.[2][5]

In vertebrates, melatonin is involved in synchronizing circadian rhythms, including sleep–wake timing and blood pressure regulation, and in control of seasonal rhythmicity including reproduction, fattening, moulting and hibernation.[6] Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant.[7][8][9] Its primary function is to defend against oxidative stress in plants[10] and bacteria. Mitochondria are the main cell organelles that produce the antioxidant melatonin,[11] which indicates that melatonin is an "ancient molecule" that primarily provided the earliest cells protection from the destructive actions of oxygen.[12][13]

In addition to its role as a natural hormone and antioxidant, melatonin is used as a dietary supplement and medication in the treatment of sleep disorders such as insomnia and circadian rhythm sleep disorders.


Biological activity

In humans, melatonin is a full agonist of melatonin receptor 1 (picomolar binding affinity) and melatonin receptor 2 (nanomolar binding affinity), both of which belong to the class of G-protein coupled receptors (GPCRs).[14][15] Melatonin receptors 1 and 2 are both Gi/o-coupled GPCRs, although melatonin receptor 1 is also Gq-coupled.[14] Melatonin also acts as a high-capacity free radical scavenger within mitochondria which also promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase via signal transduction through melatonin receptors.[16][14][17][18][19][20]

Biological functions

When eyes receive light from the sun, the pineal gland's production of melatonin is inhibited and the hormones produced keep the human awake. When the eyes do not receive light, melatonin is produced in the pineal gland and the human becomes tired.

Circadian rhythm

In animals, melatonin plays an important role in the regulation of sleep–wake cycles.[21] Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.[22] Human melatonin production decreases as a person ages.[23] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.[24]

Antioxidant

Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.[25] In vitro, melatonin acts as a direct scavenger of oxygen radicals including OH•, O2−•, and the reactive nitrogen species NO•.[26][27] In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.[27] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.[28] Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.[16][14]

Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin.[17][18][19] Due to its capacity for free radical scavenging, indirect effects on the expression of antioxidant enzymes, and its significant concentrations within mitochondria, a number of authors have indicated that melatonin has an important physiological function as a mitochondrial antioxidant.[16][17][18][19][20]

The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals.[14][20] Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).[14][20]

Immune system

While it is known that melatonin interacts with the immune system,[29][30] the details of those interactions are unclear. An anti-inflammatory effect seems to be the most relevant[citation needed]. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production and stimulate T cell expansion,[31] and by doing this, counteract acquired immunodeficiences.[32]

Weight regulation

A possible mechanism by which melatonin may regulate weight gain is through its inhibitory effect on leptin.[33] Leptin acts as a long-term indicator of energy status in the human body.[34] By suppressing leptin's actions outside of waking hours, melatonin may help restore leptin sensitivity during the daytime by alleviating leptin resistance.[33][35]

Biochemistry

Biosynthesis

Overview of melatonin biosynthesis

In animals, biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan.[36] L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase to produce 5-hydroxytryptophan. This intermediate (5-HTP) is decarboxylated by pyridoxal phosphate and 5-hydroxytryptophan decarboxylase to produce serotonin.

Serotonin is itself an important neurotransmitter, but is also converted into N-acetylserotonin by serotonin N-acetyltransferase with acetyl-CoA.[37] Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.[37]

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the synthesizing reactions are similar, but with slight variations in the last two enzymes.[38][39]

It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.[40]

Mechanism

Mechanism of melatonin biosynthesis.

In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the THB to O2 could produce a superoxide which could recombine with the THB radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O2 could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1.2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan.[41]

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.[42] PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO2. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.[43]

It has been proposed that histidine residue His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetylserotonin.[44]

N-Acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.[43][45]

Regulation

In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine.[46] Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis.[47] Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.

Blue light, principally around 460–480 nm, suppresses melatonin biosynthesis,[48] proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light.[49] The incandescent light bulb widely used in the 20th century produced relatively little blue light.[50] Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.[51] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss.[52] Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.[53]

Metabolism

Melatonin has an elimination half-life of 20 to 50 minutes.[1][2][3] In humans, melatonin is mainly metabolized to 6-hydroxymelatonin, which is conjugated with sulfate to be excreted as a waste product in urine.[54]

Measurement

For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.[55]

Use as a medication and supplement

Main article: Chemistry:Melatonin as a medication and supplement

Melatonin is used as a prescription medication and over-the-counter dietary supplement in the treatment of sleep disorders such as insomnia and circadian rhythm sleep disorders like delayed sleep phase disorder, jet lag disorder, and shift work disorder.[56] Besides melatonin, certain synthetic melatonin receptor agonists like ramelteon, tasimelteon, and agomelatine are also used in medicine.[57][58] Emerging evidence suggests melatonin may mitigate self-harm risks in adolescents. [59]

A study by the Journal of the American Medical Association published in April 2023 found that only 12% of the 30 preparations analyzed contained quantities of melatonin that were within ±10% of the declared dosage. Some supplements contained up to 347% of the declared quantity. Melatonin is an active pharmaceutical ingredient in Europe, while the U.S. in 2022 considered the substance for inclusion in pharmacy compounding. A previous study from 2022 also concluded that consuming unregulated melatonin products 'as directed' could expose children to between 40 and 130 times higher quantities of melatonin than indicated.[60]

History

Main article: Biology:History of the pineal gland

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.[61][62] As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.[63][64]

In 1958, dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.[65] In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.[66]

The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.[67]

Etymology

When Lerner and colleagues discovered melatonin, their paper in the Journal of the American Chemical Society reads:

We wish to report isolation from beef pineal glands of the active factor that can lighten skin color and inhibit MSH. It is suggested that this substance be called melatonin.[68]

The name was derived from the Greek words melas meaning "black" or "dark", and tonos meaning "labour"[69] or "colour"[70] or "suppress".[71] It follows the naming style of another skin-whitening agent, serotonin, with which Lerner and colleagues compared the effects. Serotonin was discovered in 1948 as a modulator of vascular tone (serum vasoconstrictor); hence, the name.[72] Melatonin was named likewise as it prevented darkening of the skin.[68]

Occurrence

Animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[73] located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes[74][75] 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.[76]

Many animals use the variation in duration of melatonin production each day as a seasonal clock.[77] In animals including humans,[78] 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.[78] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[79] and hamsters.[80] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone 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.

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

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors.[81] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.[81]

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.[10][82] 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.[39][83] 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.[10] In some common foods and beverages, including coffee[10] and walnuts,[84] 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.[39][85][86]

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.[87][88]

Fungal disease resistance is another role. Added melatonin increases resistance in Malus prunifolia against Diplocarpon mali.[88][89] 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.[89]

Fungi

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.[90] Danish pharmaceutical company Novo Nordisk have used genetically-modified yeast (Saccharomyces cerevisiae) to produce melatonin.[91]

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[13] most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.[12]

Novo Nordisk have used genetically-modified Escherichia coli to produce melatonin.[92][93]

Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,[94] bananas, plums, grapes, rice, cereals, herbs,[95] olive oil, wine,[96] and beer.[97] The consumption of milk and sour cherries may improve sleep quality.[98] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[99] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.[100]

References

  1. ↑ 1.0 1.1 "Melatonin". https://www.drugbank.ca/drugs/DB01065. 
  2. ↑ 2.0 2.1 2.2 "Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders". Sleep Medicine Reviews 34: 10–22. August 2017. doi:10.1016/j.smrv.2016.06.005. PMID 28648359. http://epubs.surrey.ac.uk/813219/1/Riha%20accepted%20MS%202016.pdf. 
  3. ↑ 3.0 3.1 "Melatonergic drugs in clinical practice". Arzneimittelforschung 58 (1): 1–10. 2008. doi:10.1055/s-0031-1296459. PMID 18368944. 
  4. ↑ Amaral, Fernanda Gaspar do; Cipolla-Neto, José (2018). "A brief review about melatonin, a pineal hormone". Archives of Endocrinology and Metabolism 62 (4): 472–479. doi:10.20945/2359-3997000000066. PMID 30304113. 
  5. ↑ ADHD: Non-Pharmacologic Interventions, An Issue of Child and Adolescent Psychiatric Clinics of North America, E-Book. Elsevier Health Sciences. 2014. p. 888. ISBN 978-0-323-32602-5. https://books.google.com/books?id=lNSlBAAAQBAJ&pg=PA888. 
  6. ↑ "Melatonin: therapeutic and clinical utilization". International Journal of Clinical Practice 61 (5): 835–45. May 2007. doi:10.1111/j.1742-1241.2006.01191.x. PMID 17298593. 
  7. ↑ "Molecular tools to study melatonin pathways and actions". Trends in Pharmacological Sciences 26 (8): 412–9. August 2005. doi:10.1016/j.tips.2005.06.006. PMID 15992934. 
  8. ↑ "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine 27 (2): 119–30. July 2005. doi:10.1385/ENDO:27:2:119. PMID 16217125. 
  9. ↑ "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system". Annals of the New York Academy of Sciences 939 (1): 200–15. June 2001. doi:10.1111/j.1749-6632.2001.tb03627.x. PMID 11462772. Bibcode: 2001NYASA.939..200R. 
  10. ↑ 10.0 10.1 10.2 10.3 "Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science". Journal of Experimental Botany 63 (2): 577–97. January 2012. doi:10.1093/jxb/err256. PMID 22016420. 
  11. ↑ Reiter, Russel J.; Tan, Dun Xian; Rosales-Corral, Sergio; Galano, Annia; Zhou, Xin Jia; Xu, Bing (2018). "Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions". Molecules 23 (2): 509. doi:10.3390/molecules23020509. PMID 29495303. 
  12. ↑ 12.0 12.1 Manchester, Lucien C.; Coto-Montes, Ana; Boga, Jose Antonio; Andersen, Lars Peter H.; Zhou, Zhou; Galano, Annia; Vriend, Jerry; Tan, Dun-Xian et al. (2015). "Melatonin: an ancient molecule that makes oxygen metabolically tolerable". Journal of Pineal Research 59 (4): 403–419. doi:10.1111/jpi.12267. PMID 26272235. 
  13. ↑ 13.0 13.1 Zhao, Dake; Yu, Yang; Shen, Yong; Liu, Qin; Zhao, Zhiwei; Sharma, Ramaswamy; Reiter, Russel J. (2019). "Melatonin Synthesis and Function: Evolutionary History in Animals and Plants". Frontiers in Endocrinology 10: 249. doi:10.3389/fendo.2019.00249. PMID 31057485. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 "Update on melatonin receptors: IUPHAR Review 20". British Journal of Pharmacology 173 (18): 2702–25. September 2016. doi:10.1111/bph.13536. PMID 27314810. "Hence, one melatonin molecule and its associated metabolites could scavenge a large number of reactive species, and thus, the overall antioxidant capacity of melatonin is believed to be greater than that of other well-known antioxidants, such as vitamin C and vitamin E, under in vitro or in vivo conditions (Gitto et al., 2001; Sharma and Haldar, 2006; Ortiz et al., 2013).". 
  15. ↑ "Melatonin receptors | G protein-coupled receptors | IUPHAR/BPS Guide to Pharmacology". http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=39. 
  16. ↑ 16.0 16.1 16.2 "Melatonin and human mitochondrial diseases". Journal of Research in Medical Sciences 22: 2. 2017. doi:10.4103/1735-1995.199092. PMID 28400824. 
  17. ↑ 17.0 17.1 17.2 "Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas". Cellular and Molecular Life Sciences 74 (21): 3863–3881. November 2017. doi:10.1007/s00018-017-2609-7. PMID 28864909. "melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant ... The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood.". 
  18. ↑ 18.0 18.1 18.2 "Melatonin as an antioxidant: under promises but over delivers". Journal of Pineal Research 61 (3): 253–78. October 2016. doi:10.1111/jpi.12360. PMID 27500468. "There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant.". 
  19. ↑ 19.0 19.1 19.2 "Melatonin: an ancient molecule that makes oxygen metabolically tolerable". Journal of Pineal Research 59 (4): 403–19. November 2015. doi:10.1111/jpi.12267. PMID 26272235. "While originally thought to be produced exclusively in and secreted from the vertebrate pineal gland [53], it is now known that the indole is present in many, perhaps all, vertebrate organs [54] and in organs of all plants that have been investigated [48, 55, 56]. That melatonin is not relegated solely to the pineal gland is also emphasized by the reports that it is present in invertebrates [57–59], which lack a pineal gland and some of which consist of only a single cell.". 
  20. ↑ 20.0 20.1 20.2 20.3 "Melatonin transport into mitochondria". Cellular and Molecular Life Sciences 74 (21): 3927–3940. November 2017. doi:10.1007/s00018-017-2616-8. PMID 28828619. 
  21. ↑ "A Review of Melatonin, Its Receptors and Drugs". The Eurasian Journal of Medicine 48 (2): 135–41. June 2016. doi:10.5152/eurasianjmed.2015.0267. PMID 27551178. 
  22. ↑ "Emergence and evolution of the circadian rhythm of melatonin in children". Hormone Research 59 (2): 66–72. 2003. doi:10.1159/000068571. PMID 12589109. 
  23. ↑ "Human melatonin production decreases with age". Journal of Pineal Research 3 (4): 379–88. 1986. doi:10.1111/j.1600-079X.1986.tb00760.x. PMID 3783419. 
  24. ↑ "Adolescent changes in the homeostatic and circadian regulation of sleep". Developmental Neuroscience 31 (4): 276–84. June 2009. doi:10.1159/000216538. PMID 19546564. 
  25. ↑ "Melatonin: a potent, endogenous hydroxyl radical scavenger.". Endocr. J. 1: 57–60. 1993. https://docs.google.com/document/d/e/2PACX-1vSHolKyTREzsC-RB0H-brwbUhaVP4EZBRSoZ6F7b4cOcAkutpNX3ebh0yd_QKEWRBTYVLcqpmMit3NL/pub. 
  26. ↑ "Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro". Annals of the New York Academy of Sciences 738 (1): 419–20. November 1994. doi:10.1111/j.1749-6632.1994.tb21831.x. PMID 7832450. Bibcode: 1994NYASA.738..419P. 
  27. ↑ 27.0 27.1 "The physiological function of melatonin in plants". Plant Signaling & Behavior 1 (3): 89–95. May 2006. doi:10.4161/psb.1.3.2640. PMID 19521488. Bibcode: 2006PlSiB...1...89A. 
  28. ↑ "Melatonin: a peroxyl radical scavenger more effective than vitamin E". Life Sciences 55 (15): PL271-6. 1994. doi:10.1016/0024-3205(94)00666-0. PMID 7934611. 
  29. ↑ "A review of the multiple actions of melatonin on the immune system". Endocrine 27 (2): 189–200. July 2005. doi:10.1385/ENDO:27:2:189. PMID 16217132. 
  30. ↑ "[Immunotropic properties of pineal melatonin]" (in ru). Eksperimental'naia i Klinicheskaia Farmakologiia 65 (5): 73–80. 2002. PMID 12596522. 
  31. ↑ "The modulatory role of melatonin on immune responsiveness". Current Opinion in Investigational Drugs 7 (5): 423–31. May 2006. PMID 16729718. 
  32. ↑ "The immunotherapeutic potential of melatonin". Expert Opinion on Investigational Drugs 10 (3): 467–76. March 2001. doi:10.1517/13543784.10.3.467. PMID 11227046. 
  33. ↑ 33.0 33.1 "Protective Effects of Melatonin against Obesity-Induced by Leptin Resistance". Behavioural Brain Research 417: 113598. January 2022. doi:10.1016/j.bbr.2021.113598. PMID 34563600. 
  34. ↑ "Narrative review: the role of leptin in human physiology: emerging clinical applications". Annals of Internal Medicine 152 (2): 93–100. January 2010. doi:10.7326/0003-4819-152-2-201001190-00008. PMID 20083828. 
  35. ↑ "Melatonin Absence Leads to Long-Term Leptin Resistance and Overweight in Rats". Frontiers in Endocrinology 9: 122. 2018. doi:10.3389/fendo.2018.00122. PMID 29636725. 
  36. ↑ "MetaCyc serotonin and melatonin biosynthesis". http://www.metacyc.org/META/new-image?type=PATHWAY&object=PWY-6030&detail-level=2&ENZORG=TAX-9606. 
  37. ↑ 37.0 37.1 "Melatonin: Pharmacology, Functions and Therapeutic Benefits". Current Neuropharmacology 15 (3): 434–443. April 2017. doi:10.2174/1570159X14666161228122115. PMID 28503116. 
  38. ↑ "Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources". Journal of Chemical Biology 5 (1): 5–17. January 2012. doi:10.1007/s12154-011-0064-8. PMID 22826715. 
  39. ↑ 39.0 39.1 39.2 "Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions". Journal of Experimental Botany 66 (3): 627–46. February 2015. doi:10.1093/jxb/eru386. PMID 25240067. 
  40. ↑ "Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes". Journal of Pineal Research 54 (2): 127–38. March 2013. doi:10.1111/jpi.12026. PMID 23137057. 
  41. ↑ "Mechanisms of tryptophan and tyrosine hydroxylase". IUBMB Life 65 (4): 350–7. April 2013. doi:10.1002/iub.1144. PMID 23441081. 
  42. ↑ "Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis". Biochemistry 31 (8): 2229–38. March 1992. doi:10.1021/bi00123a004. PMID 1540578. 
  43. ↑ 43.0 43.1 Medicinal Natural Products. A Biosynthetic Approach (2nd ed.). Wiley. 2002. ISBN 978-0-471-49640-3. 
  44. ↑ "Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism". Molecular Cell 3 (1): 23–32. January 1999. doi:10.1016/S1097-2765(00)80171-9. PMID 10024876. 
  45. ↑ "Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA". DNA and Cell Biology 12 (8): 715–27. October 1993. doi:10.1089/dna.1993.12.715. PMID 8397829. https://zenodo.org/record/1235255. 
  46. ↑ "Headache, drugs and sleep". Cephalalgia 34 (10): 756–66. September 2014. doi:10.1177/0333102414542662. PMID 25053748. 
  47. ↑ "Mechanisms regulating melatonin synthesis in the mammalian pineal organ". Annals of the New York Academy of Sciences 1057 (1): 372–83. December 2005. doi:10.1196/annals.1356.028. PMID 16399907. Bibcode: 2005NYASA1057..372S. 
  48. ↑ "Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor". The Journal of Neuroscience 21 (16): 6405–12. August 2001. doi:10.1523/JNEUROSCI.21-16-06405.2001. PMID 11487664. 
  49. ↑ "What's in a color? The unique human health effect of blue light". Environmental Health Perspectives 118 (1): A22-7. January 2010. doi:10.1289/ehp.118-a22. PMID 20061218. 
  50. ↑ "Recent News – Program of Computer Graphics". http://www.graphics.cornell.edu/online/measurements/source-spectra/index.html. 
  51. ↑ "Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work". The Journal of Clinical Endocrinology and Metabolism 90 (5): 2755–61. May 2005. doi:10.1210/jc.2004-2062. PMID 15713707. 
  52. ↑ "University of Houston study shows blue light glasses at night increase melatonin by 58%" (in en). 25 August 2021. https://designeroptics.com/blogs/news/university-of-houston-study-shows-blue-light-glasses-at-night-increase-melatonin-by-58. 
  53. ↑ "Amber lenses to block blue light and improve sleep: a randomized trial". Chronobiology International 26 (8): 1602–12. December 2009. doi:10.3109/07420520903523719. PMID 20030543. 
  54. ↑ Ma, Xiaochao; Idle, Jeffrey R.; Krausz, Kristopher W.; Gonzalez, Frank J. (April 2005). "Metabolism of Melatonin by Human Cytochromes P450". Drug Metabolism and Disposition 33 (4): 489–494. doi:10.1124/dmd.104.002410. PMID 15616152. https://dmd.aspetjournals.org/content/33/4/489. Retrieved 25 January 2023. 
  55. ↑ "A critical review of melatonin assays: Past and present". Journal of Pineal Research 67 (1): e12572. August 2019. doi:10.1111/jpi.12572. PMID 30919486. 
  56. ↑ "The use and misuse of exogenous melatonin in the treatment of sleep disorders". Curr Opin Pulm Med 24 (6): 543–548. November 2018. doi:10.1097/MCP.0000000000000522. PMID 30148726. 
  57. ↑ "Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders". Pharmacotherapy 36 (9): 1028–41. September 2016. doi:10.1002/phar.1822. PMID 27500861. 
  58. ↑ "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacol Rev 70 (2): 197–245. April 2018. doi:10.1124/pr.117.014381. PMID 29487083. 
  59. ↑ "Melatonin And Adolescent Self-Harm Risk". https://personalpsychology.com.au/blog/adolescent-self-harm-sleep-melatonin. 
  60. ↑ Cohen PA, Avula B, Wang Y, Katragunta K, Khan I. (April 2023) "Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US" JAMA. 329 (16): 1401–1402. doi:10.1001/jama.2023.2296. PMID 37097362
  61. ↑ "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". Journal of Pineal Research 20 (4): 175–86. May 1996. doi:10.1111/j.1600-079X.1996.tb00256.x. PMID 8836950. 
  62. ↑ "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Research 17 (5): 454–60. October 2004. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831. 
  63. ↑ Encyclopedia of dietary supplements. New York, N.Y: Marcel Dekker. 2005. pp. 457–66. ISBN 978-0-8247-5504-1. https://books.google.com/books?id=Sfmc-fRCj10C&q=Lerner+melatonin+history&pg=PA457. 
  64. ↑ "Evidences associating pineal gland function with alterations in pigmentation". J Exp Zool 23 (1): 206–24. January 1917. doi:10.1002/jez.1400230108. Bibcode: 1917JEZ....23..207M. https://books.google.com/books?id=OOM1AQAAMAAJ&pg=PA207. 
  65. ↑ "Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands". The Journal of Biological Chemistry 235 (7): 1992–7. July 1960. doi:10.1016/S0021-9258(18)69351-2. PMID 14415935. 
  66. ↑ "Daily rhythm in human urinary melatonin". Science 187 (4172): 169–71. January 1975. doi:10.1126/science.1167425. PMID 1167425. Bibcode: 1975Sci...187..169L. 
  67. ↑ Wurtman RJ, "Methods of inducing sleep using melatonin", US patent 5449683, issued 12 September 1995, assigned to Massachusetts Institute of Technology
  68. ↑ 68.0 68.1 Lerner, Aaron B.; Case, James D.; Takahashi, Yoshiyata; Lee, Teh H.; Mori, Wataru (1958). "Isolation of melatonin, the pineal gland factor that lightens melanocytes" (in en). Journal of the American Chemical Society 80 (10): 2587. doi:10.1021/ja01543a060. ISSN 0002-7863. https://pubs.acs.org/doi/abs/10.1021/ja01543a060. 
  69. ↑ Goeser, Suzanne; Ruble, James; Chandler, Linda (1997). "Melatonin: Historical and Clinical Perspectives" (in en). Journal of Pharmaceutical Care in Pain & Symptom Control 5 (1): 37–49. doi:10.1300/J088v05n01_04. http://www.tandfonline.com/doi/full/10.1300/J088v05n01_04. 
  70. ↑ Beyer, C. E.; Steketee, J. D.; Saphier, D. (1998). "Antioxidant properties of melatonin–an emerging mystery". Biochemical Pharmacology 56 (10): 1265–1272. doi:10.1016/s0006-2952(98)00180-4. ISSN 0006-2952. PMID 9825724. 
  71. ↑ Liebmann, P. M.; Wölfler, A.; Felsner, P.; Hofer, D.; Schauenstein, K. (1997). "Melatonin and the immune system". International Archives of Allergy and Immunology 112 (3): 203–211. doi:10.1159/000237455. ISSN 1018-2438. PMID 9066504. 
  72. ↑ "Serum vasoconstrictor, serotonin; isolation and characterization". The Journal of Biological Chemistry 176 (3): 1243–1251. December 1948. doi:10.1016/S0021-9258(18)57137-4. PMID 18100415. http://www.jbc.org/content/176/3/1243.short. 
  73. ↑ "Pineal melatonin: cell biology of its synthesis and of its physiological interactions". Endocrine Reviews 12 (2): 151–80. May 1991. doi:10.1210/edrv-12-2-151. PMID 1649044. 
  74. ↑ "The human circadian system in normal and disordered sleep". The Journal of Clinical Psychiatry 66 (Suppl 9): 3–9; quiz 42–3. 2005. PMID 16336035. 
  75. ↑ "The biological clock: the bodyguard of temporal homeostasis". Chronobiology International 21 (1): 1–25. January 2004. doi:10.1081/CBI-120027984. PMID 15129821. 
  76. ↑ "Sleep, circadian rhythms and health". Interface Focus 10 (3): 20190098. June 2020. doi:10.1098/rsfs.2019.0098. PMID 32382406. 
  77. ↑ "Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis". The Journal of Endocrinology 179 (1): 1–13. October 2003. doi:10.1677/joe.0.1790001. PMID 14529560. 
  78. ↑ 78.0 78.1 "Melatonin as a chronobiotic". Sleep Medicine Reviews 9 (1): 25–39. February 2005. doi:10.1016/j.smrv.2004.05.002. PMID 15649736. "Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn), it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times.". 
  79. ↑ "Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis". Australian Journal of Zoology 32 (6): 803–09. 1984. doi:10.1071/ZO9840803. 
  80. ↑ "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology 33 (1): 43–6. July 1981. doi:10.1159/000123198. PMID 7254478. 
  81. ↑ 81.0 81.1 "Genes lost during the transition from land to water in cetaceans highlight genomic changes associated with aquatic adaptations". Science Advances 5 (9): eaaw6671. September 2019. doi:10.1126/sciadv.aaw6671. PMID 31579821. Bibcode: 2019SciA....5.6671H. 
  82. ↑ "Phytomelatonin: a review". Journal of Experimental Botany 60 (1): 57–69. 1 January 2009. doi:10.1093/jxb/ern284. PMID 19033551. 
  83. ↑ "Melatonin: action as antioxidant and potential applications in human disease and aging". Toxicology 278 (1): 55–67. November 2010. doi:10.1016/j.tox.2010.04.008. PMID 20417677. 
  84. ↑ "Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood". Nutrition 21 (9): 920–4. September 2005. doi:10.1016/j.nut.2005.02.005. PMID 15979282. 
  85. ↑ "Phytomelatonin: assisting plants to survive and thrive". Molecules 20 (4): 7396–437. April 2015. doi:10.3390/molecules20047396. PMID 25911967. 
  86. ↑ "Functions of melatonin in plants: a review". Journal of Pineal Research 59 (2): 133–50. September 2015. doi:10.1111/jpi.12253. PMID 26094813. 
  87. ↑ "Melatonin-rich transgenic rice plants exhibit resistance to herbicide-induced oxidative stress". Journal of Pineal Research (Wiley) 54 (3): 258–63. April 2013. doi:10.1111/j.1600-079x.2012.01029.x. PMID 22856683. 
  88. ↑ 88.0 88.1 "Melatonin: plant growth regulator and/or biostimulator during stress?". Trends in Plant Science (Elsevier) 19 (12): 789–97. December 2014. doi:10.1016/j.tplants.2014.07.006. PMID 25156541. 
  89. ↑ 89.0 89.1 "Functions of melatonin in plants: a review". Journal of Pineal Research (Wiley) 59 (2): 133–50. September 2015. doi:10.1111/jpi.12253. PMID 26094813. 
  90. ↑ "Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases". Reviews in Endocrine & Metabolic Disorders 21 (4): 465–478. December 2020. doi:10.1007/s11154-020-09570-9. PMID 32691289. 
  91. ↑ Germann, Susanne M.; Baallal Jacobsen, Simo A.; Schneider, Konstantin; Harrison, Scott J.; Jensen, Niels B.; Chen, Xiao; Stahlhut, Steen G.; Borodina, Irina et al. (2016). "Glucose-based microbial production of the hormone melatonin in yeast Saccharomyces cerevisiae" (in en). Biotechnology Journal 11 (5): 717–724. doi:10.1002/biot.201500143. PMID 26710256. 
  92. ↑ Luo, Hao; Schneider, Konstantin; Christensen, Ulla; Lei, Yang; Herrgard, Markus; Palsson, Bernhard Ø. (2020). "Microbial Synthesis of Human-Hormone Melatonin at Gram Scales" (in en). ACS Synthetic Biology 9 (6): 1240–1245. doi:10.1021/acssynbio.0c00065. ISSN 2161-5063. PMID 32501000. https://pubs.acs.org/doi/10.1021/acssynbio.0c00065. 
  93. ↑ Arnao, Marino B.; Giraldo-Acosta, Manuela; Castejón-Castillejo, Ana; Losada-Lorán, Marta; Sánchez-Herrerías, Pablo; El Mihyaoui, Amina; Cano, Antonio; Hernández-Ruiz, Josefa (2023). "Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin". Metabolites 13 (1): 72. doi:10.3390/metabo13010072. PMID 36676997. 
  94. ↑ "Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus)". Journal of Agricultural and Food Chemistry 49 (10): 4898–902. October 2001. doi:10.1021/jf010321. PMID 11600041. 
  95. ↑ "Ingestion of Japanese plums (Prunus salicina Lindl. cv. Crimson Globe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: Nutritional and functional characterization of their content". Journal of Food and Nutrition Research 50 (4): 229–36. 2011. https://www.researchgate.net/publication/259983119. 
  96. ↑ "Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection". Journal of Pineal Research 50 (4): 374–80. May 2011. doi:10.1111/j.1600-079X.2010.00853.x. PMID 21342247. 
  97. ↑ "Melatonin in Medicinal and Food Plants". Cells 681. 5 July 2019. https://schlaf.fit/Melatonin_in_Plants_and_Food.pdf. Retrieved 2 July 2021. 
  98. ↑ "Influence of Dietary Sources of Melatonin on Sleep Quality: A Review". Journal of Food Science (Wiley) 85 (1): 5–13. January 2020. doi:10.1111/1750-3841.14952. PMID 31856339. 
  99. ↑ "Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates". Biochemistry and Molecular Biology International 35 (3): 627–34. March 1995. PMID 7773197. 
  100. ↑ "Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers". Journal of Pineal Research 55 (1): 58–64. August 2013. doi:10.1111/jpi.12025. PMID 23137025. 



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