biochemical function of melatonin

By:Evan Abdulkarim MAHMOOD

Supervisor:

Doç. Dr. Tahir KAHRAMAN

BIOCHEMICAL FUNCTIONS OF

MELATONIN

Introduction Of Melatonin

Melatonin, chemically (N-acetyl-5-methoxy tryptamine) is a hormone secreted by pineal gland in the brain. Melatonin produced by the retina and the gastrointestinal (GI) tractacts as a paracrine hormone.

It found in a wide spectrum of organisms including, animals, plants, bacteria and fungi .It helps regulate other hormones and maintains the body's circadian rhythm.

Melatonin And Age

Some researchers also believe that melatonin levels may be related to aging. For example, young children have the highest levels of nighttime melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems and tend to go to bed and wake up earlier than when they were younger.

Chemical Structure of Melatonin

Melatonin has the molecular formula (C13H16N2O2), and it has many chemical names such as (N-Acetyl-5-methoxytryptamine, 73-31-4 Circadian, 5-methoxy-n-acetyltryptamine), and the IUPAC name o melatonin is ( N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide).

2D STRUCTURE 3D CONFORMER

Synthesis of Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is primarily synthesized and secreted by the pineal gland . The synthesis of melatonin in the pineal gland involves several steps.


Melatonin is rapidly metabolized, primarily in the liver, to 6-hydroxymelatonin. A series of reactions next yield N-acetyl-5-methoxy-6-hydroxytryptamine that, depending upon the chemical environment, is conjugated to either sulfate or glucuronide

Melatonin Secretion

Under natural environment, melatonin is secreted during the night in the healthy human, as in all other species. Melatonin being a lipophilic molecule, it is not stored but directly released by diffusion of the pineal gland and released into the cerebrospinal fluid and the circulation. Although the eye contributes significally to circulating melatonin levels in a few species(sea bass, frog, quail, pigeon), retinal melatonin acts primarily within the eye

Melatonin Secretion

In humans, serum concentrations of melatonin is low during the day and is significally higher at night with peak between 02:00 am and 04:00 am, when measured with high-specificity assay. The onset of secretion usually takes place around 09:00 pm-02:00 am and the offset around 07:00 am-09:00 am in adults in the temperature zone.

Melatonin Secretion

Regulating System of Melatonin Secretion

Melatonin synthesis in the pineal gland is modulated by light/dark information that is detected by the photosensitive ganglion cells of the retina .Specifically, the signal passes through the suprachiasmatic nucleus to the pineal gland where specific “dark” and “light”-induced neural and endocrine signals co-coordinately regulate melatonin secretion. Synthesis of melatonin is inhibited by light and permitted by darkness peaking in the middle of the night in both diurnal and nocturnal animals.


The function of melatonin released from the pineal gland may be also modulated by the local release of gonadotropin-releasing hormone (GnRH) from the hypothalamus (as in the figure below)

Pathophysiology of Melatonin Secretion

Alteration of 24 hour melatonin profiles can be associated with a large variety of pathological situations. Some of the changes may have a pathogenetic relationship with major disease process. Also, since an abnormality at any level of the reregulating system unspecifically modifies melatonin secretion, other changes are more a consequence of the existing disorder.

Melatonin Catabolism

Melatonin produced by the pineal gland is released into the circulation and gains access to various fluids, tissues and cellular compartments. Because this highly lipophilic hormone is not stored in the pineal gland, the profile of its plasma levels reflects pineal activity. More than 90% of circulating melatonin is deactivated by the liver. Melatonin is first hydroxylated at the 6-position by a hepatic cytochrome.

Melatonin Catabolism

Within the brain, melatonin is degenerated via oxidative pyrrole-ring cleavage. N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), a product of this reaction, is subsequently deformylated by either arylamine formamidase or hemoperoxidase to N1-acetyl-5-methoxykynuramine (AMK)

Melatonin in food and in the gastrointestinal tract

Melatonin is a natural compound of almost ubiquitous occurrence. Its presence was demonstrated in all major taxa of organisms, as far as tested, including bacteria, unicellular eukaryotes, macroalgae, plants, fungi and invertebrate animals. Several studies dealt with melatonin in edible plants .One can conclude that relevant quantities of melatonin are present in most vegetables, fruit, nuts and cereals.


However, the precise melatonin contents are sometimes affected by some uncertainties which results from particular methodological problems arising in material from photoautotrophic organisms. First, melatonin can be easily destroyed by oxidants during extraction, and, second, false positive and false negative data are easily obtained due to the presence of secondary plant metabolites, either mimicking melatonin or interfering with it in the assays.

Metabolic Functions of Melatonin

Circadian rhythm is any biological process that displays an endogenous, entrainable oscillation of about 24 hours.

In humans and most diurnal mammals, melatonin is secreted at night with a strong circadian rhythm and maximum plasma levels that occur around 2 to 4 AM.

Circadian Rhythm Effect1


The main function of melatonin is to mediate dark signals, with possible implications in the control of circadian rhythmicity and seasonality.

With darkness at night there is melatonin secretion phases with sleep and circadian cycle.



The role of melatonin for the seasonal changes in physiology and behavior of various photoperiodic species has been extensively documented for a long time.


In winter nights there is increases duration of melatonin secretion. Summer nights melatonin secretion reduces with longer days.


Melatonin is a very potent free radical scavenger recipient and a general antioxidant. As an antioxidant melatonin binds potently the toxic hydroxyl and hyperoxide radicals. The antioxidant properties of melatonin have been proved in homogenized tissues and in living organisms

Antioxidant Effect2


The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity

Antioxidant Effect2


Any positive immunological effect is thought to result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immune competent cells. In preclinical studies, melatonin may enhance cytokine production.

Some studies also suggest that melatonin might be useful fighting infectious disease including viral and bacterial infections. In preclinical studies, melatonin may enhance cytokine production. And by doing this counteracts acquired immune deficiencies.

Immune System Effect3


Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes.

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Immune System Effect3

Melatonin Related Disease

The role of melatonin in pregnancy and embryo fetal development has hardly been discussed, but there is clear evidence of a strong connection between fetal normal development and melatonin.

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Role of Melatonin in Embryo Fetal Development1

First, the embryo and fetus are dependent on maternal melatonin, as the pineal gland becomes mature after birth. Melatonin crosses all physiological barriers without being modified, including the placental one and has been involved in placental function in animals and human.


Maternal melatonin enters the fetal circulation transplacentally providing photoperiodic information to the fetus and by that influencing the internal rhythms of the offspring.

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Role of Melatonin in Embryo Fetal Development1

Melatonin administration started prior to IVF-cycles, continued during pregnancy and was associated with improved pregnancy outcomes. Melatonin receptors are widespread in the human fetus from early fetal development. In addition, it appears that the fetuses’ sleep patterns develop in the late pregnancy, melatonin being the regulating factor.


Melatonin is produced about 90 minutes after falling asleep in a fully darkened room. It pushes you into a deeper sleep. Production is light sensitive and regulatory "sensors" have been found in the retina. Several studies have shown that irregular sleeping habits and sleeping in synthetic light, lower the production of the hormone and are also associated with higher breast cancer levels. Conversely, blind women develop less breast cancer.

Research has shown that melatonin regulates excess estrogen levels and excess IGF-1 levels. Both drive cancer and IARC has declared lack of sleep a carcinogen. Melatonin is thus an anti-cancer agent.

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Effect of Melatonin in Cancer Disease2


Studies demonstrated that melatonin inhibits cholangiocyte hyperplasia in bile duct ligation (BDL) by interaction with MT1 receptor. Specifically, administration of melatonin to cholestatic BDL decreased ductal mass and improved serum chemistry and reduced the expression of the clock genes, cyclic adenosine monophosphate cAMP levels, protein kinas A (PKA) phosphorylation in cholangiocyte.

Local modulation of melatonin synthesis may be important for management for the balance between biliary proliferation/ loss in cholangiopthies.

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Effect of Melatonin in Biliary Growth / Damage3


In support of the concept that melatonin protects the liver from selected pathological perturbations, a recent study has shown that this hormone protects against apoptosis during acetaminophen-induced acute liver failure . The findings suggest that melatonin may be an effective antioxidant agent able to reduce liver fibrosis

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Effect of Melatonin in Liver Damage4

The protective effect of melatonin on liver function has also been demonstrated during ethanol administration. For example, melatonin reduces alcoholic liver injury by reducing oxidative stress, inflammatory response, and apoptosis .


Acute pancreatitis is a disease, which could be manifested as either a mild edematous form or a more severe necrotizing pancreatitis which has a poor prognosis.

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Effect of Melatonin in Pancreatic Prevention5


Both melatonin and its precursor have been demonstrated to protect the pancreas against acute pancreatitis and to reduce pancreatic tissue damage. In the pancreas melatonin and L-tryptophan activate complex mechanisms which involve direct scavenging of the radical oxygen and nitrogen species, activation of antioxidant enzymes (catalase, superoxide dysmutase, glutation peroxidase), reduction of pro-inflammatory cytokines and prostaglandins, activation of heat shock protein, and a decrease of necrosis and increase of regeneration in the pancreas

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Acute pancreatitis is a disease, which could be manifested as either a mild edematous form or a more severe necrotizing pancreatitis which has a poor prognosis.


There are several arguments for the idea that endogenous melatonin produced in the pineal gland and in the gastrointestinal system could be the part of a native mechanisms for protecting the pancreas against acute damage:

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1

• The melatonin precursor L-tryptophan exerts similar protective effect as melatonin

2• Application of the melatonin receptor antagonist, luzindole aggravates acute pancreatitis

3• Pinealectomy results in the exacerbation of acute pancreatitis

4

• Low melatonin plasma levels are associated with an increased risk of severe acute pancreatitis.


A deficient production of melatonin or (Hypomelatonism) can result in anxiety and mood disorders, lowered basal body temperature insomnia, elevated estrogen/progesterone ratio, and immune suppression associated with cancer.

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Melatonin Deficiency and Excess6

DEFICIENCY


And there are many reasons that cause to low melatonin levels such as (alcohol, Vitamin B12, caffeine, Beta-blocker medications, Cigarettes, Frequent stress, antidepressants).

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DEFICIENCY

Alcohol Vitamin B12 Caffeine

Beta-Blocker

medicationsCigarettes

Frequent stress

Anti- depressants


Excess melatonin or we can say (hypermelatonism) is associated with seasonal affective disorder (SAD), lowered estrogen/progesterone ratio, low thyroid and adrenal function, and hypotension, extreme fatigue and lack of energy, increased need for sleep, carbohydrate cravings, exposure to light improve

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EXCESS


Melatonin is known to possess several properties of value for healthy aging, as a direct and indirect antioxidant, protectant and modulator of mitochondrial function, anti excitotoxic agent, enhancer of circadian amplitude, immune modulator and neuroprotector.

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Melatonin and Other Related Disease7


It is level tend to decrease in the course of senescence and are more strongly reduced in several neurodegenerative disorders, especially Alzheimer’s disease, and in disease related to insulin resistance such as diabetes type 2. Although the role of melatonin in aging and age-related diseases has been repeatedly discussed, the newly emerged concept of inflammaging, that is, the contribution of low-grade inflammation to senescence progression has not been the focus of melatonin research

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Melatonin and Other Related Disease7

SUMAMARY

References

Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W, (1958) Isolation of melatonin, the pineal factor that lightens melanocytes. J Am Chem Sci, 89, 2857–2858.

Bubenik, G.A., (2002) Gastrointestinal melatonin: Localization, function, and clinical relevance. Dig Dis Sci, 47, 2336–2348.

Hardeland R, Poeggeler B: (2003) Non-vertebrate melatonin. J Pineal Res, 34:233-241.

Maestroni GJ. : (2001) The immunotherapeutic potential of melatonin. Expert Open Investing Drugs, 10(3):467-76.

Tahan V, Ozaras R, Canbakan B.: (2004) Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats. J PinealRes ;37:78-84.

Renzi A, DeMorrow S, Onori P : (2013) Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses ofcholangiocytes in rats. Hepatology; 57:1130-41.

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References

Tahan V, Ozaras R, Canbakan B.: (2004) Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats. J PinealRes ;37:78-84.

Hu S, Yin S, Jiang X.: (2009) Melatonin protects against alcoholic liver injury by attenuating oxidative stress, inflammatory response, and apoptosis. Eur J Pharmacol ;616:287-92.

Ru¨ diger Hardeland a , Daniel P. Cardinali b, Gregory M. Brown c, Seithikurippu R. Pandi-Perumal, : (2015) Melatonin and brain inflammaging, Progress in Neurobiology 127–128 46–63.

Klein DC, Ganguly S, Coon S,. (2002) Proteins and photoneuroendocrine transduction: role in controlling the daily rhythm in melatonin. Biochem Soc Trans; 30:365-73.

Jolanta B. Zawilska, (2009) Melatonin and biological rhythms. Pharmacological Reports, , 61, 383–410.

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biochemical function of melatonin

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