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Semin Clin Neuropsychiatry ; 5 : 44— Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet ; : Since plants cannot behaviorally avoid extremely stressful conditions, they require extra protection from stress; hence, the biosynthesis of tryptophan is presumably retained in plants to ensure that melatonin is available for relieving oxidative stress levels under environmentally-stressful conditions.
Beginning with tryptophan, melatonin biosynthesis includes four enzymatic steps in all organisms 22 , During its evolution lasting billions of years, the pattern of the melatonin synthesis became diversified Figure 4. Tryptophan is first converted to serotonin which involves decarboxylation and hydroxylation. There are two strategies for the synthesis of serotonin that leads to melatonin production in different taxa. The biosynthetic pathway of serotonin in microorganisms and plants is different from that of vertebrates.
Tryptophan is decarboxylated to tryptamine by tryptophan decarboxylase TDC , followed by serotonin biosynthesis catalyzed by tryptamine 5-hydroxylase T5H in plants , In contrast, rather than tryptophan decarboxylation being the initial step in serotonin production, animals first hydroxylate tryptophan using tryptophan hydroxylase TPH to form 5-hydroxytryptophan and then 5-hydroxytryptophan is decarboxylated by aromatic amino acid decarboxylase AADC to form serotonin 7.
Figure 4. Pathways of melatonin synthesis in different plant left and animal right taxa. Depending on the organism, not all of the events necessarily take place in the chloroplasts or mitochondria of every species.
For the species, plant and animal, that have been investigated, the published data provide strong evidence that these organelles are critically involved with melatonin production. Between tryptophan and melatonin, serotonin is a key intermediate after which the biosynthetic process utilizes two potential pathways, each of which includes two consecutive enzymatic steps to generate melatonin 15 , Differing from the formation of serotonin, the two alternative pathways for the conversion of serotonin to melatonin, likely occur in both plants and animals as well as in the microorganisms.
However, different homologs of NAT have been detected between plants and animals, as well as ASMT in the two groups, revealing their different origins during evolution , — NAT seems to have originated independently as indicated by the few shared amino acid residues between animals and plants as well as between primitive cyanobacteria and archaea 24 , Thus, the enzymes controlling the biosynthetic steps of melatonin seem to have different origins at the emergence of melatonin; these enzymes further evolved divergently after endosymbiosis.
As already mentioned, the intermediate processes in melatonin production display a variety of differences among taxa. The present-day organisms possess diverse melatonin biosynthetic pathways. The enzymes that produce melatonin may play roles in catalyzing different substrates. Beyond the four key enzymes, other evolved enzymes are reported to directly participate in the biosynthesis of melatonin. Apart from the classic enzymes strictly required for the melatonin biosynthetic pathways, Lee et al.
The observations that the NAT protein, the rate-limiting enzyme of melatonin synthesis, is abundantly located in mitochondria of animals and chloroplasts of plants further support the different origins of the melatonin biosynthetic enzymes as a result of endosymbiosis 26 , , Furthermore, the DNA sequences and protein residues of cyanobacterium, a plant-type species, and rice are closely related, implying that the plant NAT gene was likely endosymbiotically-derived from cyanobacteria , NAT genes of other eukaryotic organisms including fungi, invertebrates, and vertebrates seemingly evolved from Rhodospirillum rubrum the presumed precursor of mitochondria or closely related species since their NAT genes share similarity to some extent 24 , , With endosymbiotic evolution, the function of melatonin synthesis was carried into multicellular organisms.
In terms of function, melatonin produced in these two organelles most likely detoxifies excessive ROS and reactive nitrogen species RNS generated during oxidative phosphorylation and other metabolic actions 55 , The production of melatonin in mitochondria provides maximal on-site protection of these critical organelles Figure 4.
In plants, melatonin in chloroplasts provides a similar defense against oxidative stress with subsequent evolution after endosymbiosis. The melatonin-associated genes of the incorporated bacteria were gradually transferred from both mitochondria and chloroplasts to the nuclear genome of each host 24 , — , While mitochondria and chloroplasts are considered major sites of melatonin synthesis, it does not preclude the possibility that some melatonin is not also formed in the cytosol ; also, see below.
With subsequent evolutionary processes, melatonin-related genes were modified by mutations and in response to natural selective pressures in different species 24 , , Specifically, the major structural differences of the melatonin synthases among phylogenetically distant species are the regulatory regions which could further influence the subcellular localization of these proteins 7 , At least in plants, the subcellular localization analysis documented that the rate-limiting enzyme for melatonin synthesis, NAT, is found in both chloroplasts and mitochondria This subcellular location of melatonin synthesis enzymes suggests that during evolution Figure 2 , the sites of melatonin synthesis became more diverse and extended to the cytoplasm and endoplasmic reticulum This divergent distribution of melatonin production shows a good relationship with the transformation from prokaryotic cell to eukaryotic cell.
Regarding the efficiency of melatonin biosynthesis, the present biosynthetic model is consistent with adequate substrate availability. For example, acetyl-CoA, a key substrate for melatonin production, is synthesized in the mitochondria through pyruvate dehydrogenase complex reaction 39 , , Furthermore, the different subcellular sites of melatonin synthetase avoid substrate competition by other enzymes preferring the same substrate 13 , 22 , Thus, multiple subcellular sites of melatonin biosynthesis in both plants and animals could promote synthetic efficiency of this essential molecule The presence of melatonin at several sites correlates with its biological functions.
As in animals, h rhythms have been described in plants, e. Also, the dinoflagellate Lingulodinium and numerous other microalgae including chlorophyceans like plants, members of viridiplantae , exhibit robust circadian rhythms of melatonin In comparison to animal cells, plant cells contain much higher levels of melatonin, probably because they have two melatonin producing organelles, mitochondria and chloroplasts 77 , , In some species such as in Glycyrrhiza uralensis , cranberry and several medicinal herbs melatonin levels are reportedly several orders of magnitude higher than those in the serum of animals.
This may relate to the high environmental stress condition under which this plant normally grows. The immobility of plants results in them being subjected to more unavoidable environmental stressors, causing elevated ROS production and oxidative damage. Thus, they require additional protection from stressors by means of intrinsic mechanisms including high levels of endogenously-produced antioxidants, such as melatonin This speculation is supported by the observation that a variety of environmental insults induce a dramatic increase in melatonin levels in plants 24 , , Under some conditions, stressful situations may also induce melatonin production in animals, e.
Also, plant cells generally have higher levels of melatonin than animal cells; this likely relates to the fact that plant cells have two sources of melatonin mitochondria and chloroplasts while animal cells have a single source.
The presence of melatonin in both plants and animals raises the question as to whether animals and plants have different mechanisms for modulating the biosynthesis of this indole-containing compound.
Current data indicate that the regulatory mechanisms of melatonin synthesis are fundamentally different between animals and plants Figure 5. Hence, melatonin synthesis in some plants is non-rhythmic, as in the mitochondria of animals Figure 5. A summary of what is known concerning the molecular mechanism governing melatonin production in plant cells and animal cells.
In vertebrates, light detection by the retinas suppresses the activity of NAT and melatonin production , In plants, there is positive correlation between light intensity and melatonin levels with plants growing in habitats exposed to high light intensities, such as Mediterranean or alpine environments, usually having higher melatonin levels than the same or related species growing in other locations In some species, melatonin was reported to be enhanced by darkness of even short duration, e.
Moreover, heat-induced elevation of melatonin was antagonized by light in Oryza In addition to these exceptions, the signal transduction pathways and regulatory mechanisms in vertebrates differ substantially from those in plants. The major regulatory components of melatonin synthesis in mammals, e. As noted above, the biosynthesis of melatonin is closely associated with four successive enzymes leading to the production of this compound. NAT usually is believed to be the rate-limiting enzyme in pineal melatonin synthesis in vertebrates, although ASMT may limit this level around the nocturnal melatonin maximum For plants, under most circumstances, NAT activity correlates well with the quantity of melatonin produced.
In rice seedlings, however, melatonin was reported to be highest at the time of enhanced ASMT expression , Typical for animals, the activities of NAT and melatonin production usually exhibit a good positive relationship , The regulation of NAT in the pineal gland depends on the animal taxa examined.
In many mammals, NAT gene expression in the pineal is either up- or down-regulated by the signals received from the suprachiasmatic nucleus SCN while in some species with a predominantly transcriptional control of NAT, its mRNA levels are stimulated up to two orders of magnitude For primates and ungulates, NAT is mainly controlled post-translationally by phosphorylation and dephosphorylation, and stabilization of the phosphorylated form by a protein While the four successive enzymes positively regulate the pineal concentration of melatonin in all organisms, the overexpression of melatonin biosynthetic genes, such as TDC, NAT , and ASMT do not always lead to the accumulation of melatonin in plants 33 , , , , , Recently, the ASDAC gene was found to catalyze the conversion of N -acetylserotonin to serotonin, a reverse reaction from the usual melatonin biosynthetic pathway in plants Especially in plants, melatonin is maintained at a relatively constant level under normal conditions; however, it can be greatly and rapidly upregulated in response to unfavorable conditions such as cold, heat, salt, drought, oxidative and nutrient stress, and bacterial infection , — The underlying mechanisms for the rapid regulation of melatonin production have not been identified including the translation and post-translational regulation of melatonin synthesis enzymes, and the upstream transcription factors of these rate-limiting enzymes or isoenzymes , Melatonin biosynthesis genes may have a role at the transcriptional level to control the content of melatonin Figure 5.
For this process, different taxa evolved divergently to work with other factors for self-development or coping with stressful conditions. Activator protein-1 AP-1 is a stress-responsive transcription factor that can be regulated by oxidative stress in many cell types Interestingly, stress uniformly stimulates glucocorticoid production in organisms Glucocorticoids upregulate the transcriptional activity AP-1 and thereby promote gene expression for melatonin synthesis , This motif was not found in NAT genes from other species, including mouse, rat, and zebrafish In addition, the cone-rod homeobox Crx transcription factor was reported to regulate the expression of NAT in the mouse pineal gland.
For plants, limited information related to transcriptional regulation is available compared with that of animals. Evidence from recent studies show that a multifunctional enzyme, namely caffeic acid O-methyltransferase COMT , can also catalyze the last step of melatonin biosynthesis Cai et al. For cassava, three TFs were found to modulate melatonin biosynthesis. The acquisition of additional functions by melatonin, which is believed to have originally evolved to provide molecular protection from free radicals, occurred over a very long evolutionary period.
It is theorized that melatonin first appeared in bacteria about 3. When these melatonin-synthesizing bacteria were phagocytized by early eukaryotes as food, over time they established a symbiotic association with their hosts and developed into mitochondria and chloroplasts. Since the bacteria that were ingested had the ability to synthesize melatonin, this important function was retained by the mitochondria and chloroplasts.
As a consequence, we hypothesize that these organelles have produced melatonin in every plant and animal species that has ever existed and that this occurs in present day animal and plant cells as well. Thus, every cell that possesses mitochondria animals and plants or chloroplasts plants , we feel, has the capacity to produce melatonin. Melatonin at these sites is important to provide protection against free radicals which are abundantly generated in these organelles.
Over its very long evolutionary history, melatonin has acquired other essential functions that have been retained by this physiologically-diverse molecule. Tryptophan is the starting molecule for melatonin production in cell species. The sequence of the enzymatic steps that convert tryptophan to melatonin, however, varies among species.
These steps include hydroxylation, decarboxylation, acetylation, and methylation. In some plant species, melatonin may not be the end product; in at least one variety of rice, melatonin can be hydroxylated at either 2, 4, or 6 position with 2-hydroxymelatonin possessing significant antioxidant activity, like melatonin itself.
While the synthetic pathway of melatonin has changed throughout evolution and differs among plant and animal species, the structure of melatonin persists as originally designed in bacteria billions of years ago.
It is pointed out, however, that what is known about melatonin synthesis has come primarily from mammals and the pathway in other vertebrates has been sparingly investigated. Moreover, the pathway of melatonin production in invertebrates remains to be examined. RR initiated the review and checked all drafts of the report. QL and RS prepared figures for the article and read the final version.
ZZ and RS participated in the discussion of the functional evolution of melatonin. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Isolation of melatonin, the pineal gland factor that lightens melanocyteS 1. J Am Chem Soc. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry.
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J Cell Physiol. Current review, in commemoration of 50 years of discovery of melatonin, while revisiting the established dogmas, summarizes current information on biosynthesis, secretion, metabolism and molecular mechanism of action of melatonin at cellular level and highlights the recent research on its role in human physiology and clinical biology.
Abstract Melatonin N-acetylmethoxytryptamine was first purified and characterized from the bovine pineal gland extract by Aron Lerner and co-workers in Fibers from the hypothalamus descend to the spinal cord and ultimately project to the superior cervical ganglia, from which post-ganglionic neurons ascend back to the pineal gland.
Thus, the pineal is similar to the adrenal medulla in the sense that it transduces signals from the sympathetic nervous system into a hormonal signal. The precursor to melatonin is serotonin, a neurotransmitter that itself is derived from the amino acid tryptophan. Within the pineal gland, serotonin is acetylated and then methylated to yield melatonin. Synthesis and secretion of melatonin is dramatically affected by light exposure to the eyes.
The fundamental pattern observed is that serum concentrations of melatonin are low during the daylight hours, and increase to a peak during the dark. Examples of the circadian rhythm in melatonin secretion in humans is depicted in the figure to the right adapted from Vaughn, et al, J Clin Endo Metab , The dark gray bars represent night, and serum melatonin levels are shown for two individuals yellow versus light blue.
Note that blood levels of melatonin are essentially undetectable during daytime, but rise sharply during the dark. Very similar patterns are seen in other species. The duration of melatonin secretion each day is directly proportional to the length of the night. The mechanism behind this pattern of secretion during the dark cycle is that activity of the rate-limiting enzyme in melatonin synthesis - serotonin N-acetyltransferase NAT - is low during daylight and peaks during the dark phase.
Activity of the other enzyme involved in synthesis of melatonin from serotonin - the methyltransferase - does not show regulation by pattern of light exposure.
Two melatonin receptors have been identified from mammals designated Mel1A and Mel1B that are differentially expressed in different tissues and probably participate in implementing differing biologic effects. These are G protein-coupled cell surface receptors.
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