Melatonin is a
natural product
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
found in plants and animals. It is primarily known in animals as a
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
released by the
pineal gland
The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...
in the brain at night, and has long been associated with control of the
sleep–wake cycle
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
.
In vertebrates, melatonin is involved in
synchronizing circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
s, including sleep–wake timing and
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
regulation, and in control of seasonal rhythmicity including reproduction, fattening, moulting and hibernation.
Many of its effects are through activation of the
melatonin receptor
Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other ma ...
s, while others are due to its role as an
antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
.
In plants, it functions to defend against
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
.
It is also present in various foods.
Melatonin was discovered in 1958.
In addition to its role as a natural hormone, melatonin is used as a
dietary supplement
A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
and
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
in the treatment of
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s such as
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
and
circadian rhythm sleep disorders; for information on melatonin as a supplement and medication, see the
melatonin as a medication and supplement
Melatonin is a dietary supplement and medication as well as naturally occurring hormone. As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement, it is often used for the short-term tre ...
article.
Biological activity
In humans, melatonin is a
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of
melatonin receptor 1
Melatonin receptor type 1A is a protein that in humans is encoded by the ''MTNR1A'' gene.
Function
This gene encodes the MT1 protein, one of two high-affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. ...
(
picomolar
Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solu ...
binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
) and
melatonin receptor 2
Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the ''MTNR1B'' gene.
Function
This gene encodes the MT2 protein, one of two high-affinity forms of a receptor for melatonin, the primary hormone secreted by ...
(nanomolar binding affinity), both of which belong to the class of
G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
s (GPCRs).
Melatonin receptors 1 and 2 are both
Gi/o-coupled GPCRs, although melatonin receptor 1 is also
Gq-coupled.
Melatonin also acts as a high-capacity
free radical scavenger within
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
which also promotes the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of antioxidant enzymes such as
superoxide dismutase
Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen me ...
,
glutathione peroxidase
Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
,
glutathione reductase
Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase (EC 1.8.1.7) catalyzes the reduction of glutathione disulfide ( GSSG) to the sulfhydryl f ...
, and
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
via
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
through
melatonin receptor
Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other ma ...
s.
Biological functions
Circadian rhythm
In animals, melatonin plays an important role in the regulation of
sleep–wake cycles.
Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.
Human melatonin production decreases as a person ages.
Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to
later sleeping and waking times.
Antioxidant
Melatonin was first reported as a potent antioxidant and
free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
scavenger in 1993. In vitro, melatonin acts as a direct scavenger of oxygen radicals including OH
•, O
2−•, and the reactive nitrogen species NO
•.
In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.
Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.
Via
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
through
melatonin receptor
Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other ma ...
s, melatonin promotes the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of antioxidant
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s such as
superoxide dismutase
Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen me ...
,
glutathione peroxidase
Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
,
glutathione reductase
Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase (EC 1.8.1.7) catalyzes the reduction of glutathione disulfide ( GSSG) to the sulfhydryl f ...
, and
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
.
Melatonin occurs at high concentrations within
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
l fluid which greatly exceed the
plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
concentration of melatonin.
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.
The melatonin metabolites produced via the reaction of melatonin with
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
or
reactive nitrogen species
Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (•NO) and superoxide (O2•−) produced via the enzymatic activity of inducible nitric oxide synthase 2 ( NOS2) and NADPH oxidase respectivel ...
also react with and reduce free radicals.
Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).
Immune system
While it is known that melatonin interacts with the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
,
the details of those interactions are unclear. An
anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
effect seems to be the most relevant. 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
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
production and stimulate T cell expansion,
and by doing this, counteract
acquired immunodeficiences
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
.
Weight regulation
A possible mechanism by which melatonin may regulate weight gain is through its inhibitory effect on
leptin
Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...
.
Leptin acts as a long-term indicator of energy status in the human body. By suppressing leptin's actions outside of waking hours, melatonin may help restore leptin sensitivity during the daytime by alleviating leptin resistance.
Biochemistry
Biosynthesis
![Mealtonin biosynth](https://upload.wikimedia.org/wikipedia/commons/a/af/Melatonin_biosynth.jpg)
In animals, biosynthesis of melatonin occurs through
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
,
decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
,
acetylation
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
and a
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
starting with
L-tryptophan.
L-tryptophan is produced in the
shikimate pathway
The shikimate pathway (shikimic acid pathway) is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids (tryptophan, phenylalanine, and tyrosine) ...
from
chorismate
Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for:
* The aromatic amino acids phenylalanine, tryptophan, and tyrosine
* Indole, indole d ...
or is acquired from
protein catabolism
In molecular biology, protein catabolism is the breakdown of proteins into smaller peptides and ultimately into amino acids. Protein catabolism is a key function of digestion process. Protein catabolism often begins with pepsin, which converts p ...
. First
L-tryptophan is hydroxylated on the
indole ring by
tryptophan hydroxylase
Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aro ...
to produce
5-hydroxytryptophan
5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.
Uses
5-HTP is sold over the counter i ...
. This intermediate (5-HTP) is decarboxylated by
pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
and
5-hydroxytryptophan decarboxylase to produce
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
.
Serotonin is itself an important
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
, but is also converted into
''N''-acetylserotonin by
serotonin ''N''-acetyltransferase with
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
.
Hydroxyindole ''O''-methyltransferase and
''S''-adenosyl methionine convert ''N''-acetylserotonin into melatonin through methylation of the hydroxyl group.
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
Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/ ...
, and in
photosynthetic cells with carbon dioxide. The rest of the synthesizing reactions are similar, but with slight variations in the last two enzymes.
It has been hypothesized that melatonin is made in the mitochondria and
chloroplast
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
s.
Mechanism
![Melatonin mechanism](https://upload.wikimedia.org/wikipedia/commons/9/9f/Melatonin_mechanism.jpg)
In order to hydroxylate L-tryptophan, the cofactor
tetrahydrobiopterin
Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin ...
(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 O
2 could produce a
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
which could recombine with the THB
radical
Radical may refer to:
Politics and ideology Politics
*Radical politics, the political intent of fundamental societal change
*Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
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. O
2 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
A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encountere ...
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
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to saturate ...
to furnish 5-hydroxy-L-tryptophan.
A decarboxylase with cofactor
pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
(PLP) removes CO
2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine. PLP forms an
imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
with the amino acid derivative. The amine on the pyridine is
protonated
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid, ...
and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO
2. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.
It has been proposed that
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
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
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
from
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
serves as a good
leaving group In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited t ...
when
attacked by a general base to give N-acetylserotonin.
N-Acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce
S-adenosyl homocysteine (SAH) and melatonin.
Regulation
In vertebrates, melatonin secretion is regulated by activation of the
beta-1 adrenergic receptor
The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, is a beta-adrenergic receptor, and also denotes the human gene encoding it. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein and is expres ...
by
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
.
Norepinephrine elevates the intracellular
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
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
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
. Production of melatonin is again started in the evening at the point called the
dim-light melatonin onset.
Blue light, principally around , suppresses melatonin biosynthesis,
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. The
incandescent light bulb
An incandescent light bulb, incandescent lamp or incandescent light globe is an electric light with a wire filament heated until it glows. The filament is enclosed in a glass bulb with a vacuum or inert gas to protect the filament from oxida ...
widely used in the 20th century produced relatively little blue light. Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.
Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. 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.
Metabolism
Melatonin has an
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
of 20 to 50minutes.
Measurement
For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.
Use as a medication and supplement
Melatonin is used as a
prescription medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
and
over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
dietary supplement
A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
in the treatment of
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s such as
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
and
circadian rhythm sleep disorders like
delayed sleep phase disorder
Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a delaying of a person's circadian rhythm (biological clock) compared to those of societal norms. The diso ...
,
jet lag disorder, and
shift work disorder.
Besides melatonin, certain
synthetic melatonin receptor agonist
Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The disc ...
s like
ramelteon
Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. ...
,
tasimelteon
Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder (also called non-24, N24 and N24HSWD). In June 2014, th ...
, and
agomelatine are also used in medicine.
History
Melatonin was first discovered in connection to the mechanism by which some
amphibians
Amphibians are four-limbed and ectothermic vertebrates of the class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terrestrial, fossorial, arbore ...
and
reptiles
Reptiles, as most commonly defined are the animals in the Class (biology), class Reptilia ( ), a paraphyletic grouping comprising all sauropsid, sauropsids except birds. Living reptiles comprise turtles, crocodilians, Squamata, squamates (lizar ...
change the color of their skin.
As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened
tadpole
A tadpole is the larval stage in the biological life cycle of an amphibian. Most tadpoles are fully aquatic, though some species of amphibians have tadpoles that are terrestrial. Tadpoles have some fish-like features that may not be found i ...
skin by contracting the dark
epidermal
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...
melanophores
Chromatophores are cells that produce color, of which many types are pigment-containing cells, or groups of cells, found in a wide range of animals including amphibians, fish, reptiles, crustaceans and cephalopods. Mammals and birds, in contrast, ...
.
In 1958,
dermatology
Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medical ...
professor
Aaron B. Lerner Aaron Bunsen Lerner (September 21, 1920 – February 3, 2007), also known in scientific articles as Aaron B. Lerner, was an American physician, researcher and professor.
Life and career
Born in 1920 in Minneapolis, Lerner received his medical degre ...
and colleagues at
Yale University
Yale University is a private research university in New Haven, Connecticut. Established in 1701 as the Collegiate School, it is the third-oldest institution of higher education in the United States and among the most prestigious in the wo ...
, in the hope that a substance from the pineal might be useful in treating
skin diseases
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sy ...
, isolated the hormone from
bovine pineal gland extracts and named it melatonin.
In the mid-70s Lynch ''et al.'' demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.
In other species
Other animals
In vertebrates, melatonin is produced in darkness, thus usually at night, by the
pineal gland
The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...
, a small
endocrine gland
Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid ...
located in the center of the brain but outside the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. Light/dark information reaches the
suprachiasmatic nuclei
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
from retinal
photosensitive ganglion cell
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence ...
s 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
Nocturnality is an animal behavior characterized by being active during the night and sleeping during the day. The common adjective is "nocturnal", versus diurnal meaning the opposite.
Nocturnal creatures generally have highly developed sens ...
(night-active) animals and sleep in diurnal ones including humans.
Many animals 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
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous
Endogenous subs ...
) seasonal functions such as reproduction, behavior, coat growth, and camouflage
coloring in seasonal animals.
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
The Mynah Birds was a Canadian Rhythm and blues, R&B band formed in Toronto, Ontario, that was active from 1964 to 1967.Chong. 2005. Although the band never released an album, it is notable as featuring a number of musicians, such as Rick James ...
and hamsters.
Melatonin can suppress
libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
by inhibiting secretion of
luteinizing hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
and
follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...
from the
anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
gland, especially in mammals that have a
breeding
Breeding is sexual reproduction that produces offspring, usually animals or plants. It can only occur between a male and a female animal or plant.
Breeding may refer to:
* Animal husbandry, through selected specimens such as dogs, horses, and ra ...
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
Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...
, lowering its levels.
Cetacean
Cetacea (; , ) is an infraorder of aquatic mammals that includes whales, dolphins, and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively carnivorous diet. They propel them ...
s 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
The vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...
at a time). Similar trends have been found in
sirenia
The Sirenia (), commonly referred to as sea-cows or sirenians, are an order of fully aquatic, herbivorous mammals that inhabit swamps, rivers, estuaries, marine wetlands, and coastal marine waters. The Sirenia currently comprise two distinct f ...
ns.
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.
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.
In some common foods and beverages, including coffee
and walnuts, 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
Soil salinity is the salt content in the soil; the process of increasing the salt content is known as salinization. Salts occur naturally within soils and water. Salination can be caused by natural processes such as mineral weathering or by the ...
, drought, etc.
Herbicide
Herbicides (, ), also commonly known as weedkillers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page fo ...
-induced
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
has been experimentally mitigated ''in vivo'' in a high-melatonin
transgenic rice.
Fungal disease resistance is another role. Added melatonin increases
resistance in ''
Malus prunifolia'' against ''
Diplocarpon mali''.
Also acts as a
growth inhibitor
Growth may refer to:
Biology
* Auxology, the study of all aspects of human physical growth
* Bacterial growth
* Cell growth
* Growth hormone, a peptide hormone that stimulates growth
* Human development (biology)
* Plant growth
* Secondary growt ...
on
fungal pathogens including ''
Alternaria
''Alternaria'' is a genus of Deuteromycetes fungi. All species are known as major plant pathogens. They are also common allergens in humans, growing indoors and causing hay fever or hypersensitivity reactions that sometimes lead to asthma. They ...
'', ''
Botrytis'', and ''
Fusarium
''Fusarium'' is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the soil mi ...
'' spp. Decreases the speed of infection. As a
seed treatment
In agriculture and horticulture, a seed treatment is any additional material added to the seed. By the amount of material added, it can be divided into:
* A seed dressing, typically containing a "protectant" ( pesticide) applied to the seed and p ...
, protects ''
Lupinus albus
''Lupinus albus'', commonly known as the white lupin or field lupine, is a member of the genus '' Lupinus'' in the family Fabaceae. It is a traditional pulse cultivated in the Mediterranean region.
Description
The white lupin is annual, mo ...
'' from fungi. Dramatically slows
''Pseudomonas syringae tomato'' DC3000 infecting ''Arabidopsis thaliana'' and
infecting ''Nicotiana benthamiana''.
Fungi
Melatonin has been observed to reduce stress tolerance in ''
Phytophthora infestans
''Phytophthora infestans'' is an oomycete or water mold, a fungus-like microorganism that causes the serious potato and tomato disease known as late blight or potato blight. Early blight, caused by ''Alternaria solani'', is also often called "pot ...
'' in plant-pathogen systems.
Occurrence
Food products
Naturally-occurring melatonin has been reported in foods including
tart cherries to about 0.17–13.46 ng/g,
bananas, plums, grapes, rice, cereals, herbs, olive oil,
wine
Wine is an alcoholic drink typically made from fermented grapes. Yeast consumes the sugar in the grapes and converts it to ethanol and carbon dioxide, releasing heat in the process. Different varieties of grapes and strains of yeasts are m ...
,
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
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*
*
{{Authority control
Acetamides
Antioxidants
Aromatase inhibitors
Circadian rhythm
Hormones of the pineal gland
Melatonin receptor agonists
Methoxy compounds
Mexamines
Tryptamine alkaloids
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