Melatonin is a highly conserved molecule. Its presence can be traced back to ancient photosynthetic prokaryotes. A primitive and primary function of melatonin is that it acts as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. The receptor-dependent functions of melatonin were subsequently acquired during evolution. In the current review, we focus on melatonin metabolism which includes the synthetic rate-limiting enzymes, synthetic sites, potential regulatory mechanisms, bioavailability in humans, mechanisms of breakdown and functions of its metabolites. Recent evidence indicates that the original melatonin metabolite may be N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) rather than its commonly measured urinary excretory product 6-hydroxymelatonin sulfate. Numerous pathways for AFMK formation have been identified both in vitro and in vivo. These include enzymatic and pseudo-enzymatic pathways, interactions with reactive oxygen species (ROS)/reactive nitrogen species (RNS) and with ultraviolet irradiation. AFMK is present in mammals including humans, and is the only detectable melatonin metabolite in unicellular organisms and metazoans. 6-Hydroxymelatonin sulfate has not been observed in these low evolutionary-ranked organisms. This implies that AFMK evolved earlier in evolution than 6-hydroxymelatonin sulfate as a melatonin metabolite. Via the AFMK pathway, a single melatonin molecule is reported to scavenge up to 10 ROS/RNS. That the free radical scavenging capacity of melatonin extends to its secondary, tertiary and quaternary metabolites is now documented. It appears that melatonin's interaction with ROS/RNS is a prolonged process that involves many of its derivatives. The process by which melatonin and its metabolites successively scavenge ROS/RNS is referred as the free radical scavenging cascade. This cascade reaction is a novel property of melatonin and explains how it differs from other conventional antioxidants. This cascade reaction makes melatonin highly effective, even at low concentrations, in protecting organisms from oxidative stress. In accordance with its protective function, substantial amounts of melatonin are found in tissues and organs which are frequently exposed to the hostile environmental insults such as the gut and skin or organs which have high oxygen consumption such as the brain. In addition, melatonin production may be upregulated by low intensity stressors such as dietary restriction in rats and exercise in humans. Intensive oxidative stress results in a rapid drop of circulating melatonin levels. This melatonin decline is not related to its reduced synthesis but to its rapid consumption, i.e. circulating melatonin is rapidly metabolized by interaction with ROS/RNS induced by stress. Rapid melatonin consumption during elevated stress may serve as a protective mechanism of organisms in which melatonin is used as a first-line defensive molecule against oxidative damage. The oxidative status of organisms modifies melatonin metabolism. It has been reported that the higher the oxidative state, the more AFMK is produced. The ratio of AFMK and another melatonin metabolite, cyclic 3-hydroxymelatonin, may serve as an indicator of the level of oxidative stress in organisms.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2006.00407.x

One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?

Melatonin was discovered to be a direct free radical scavenger less than 10 years ago. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, it stimulates several antioxidative enzymes which increase its efficiency as an antioxidant. In terms of direct free radical scavenging, melatonin interacts with the highly toxic hydroxyl radical with a rate constant equivalent to that of other highly efficient hydroxyl radical scavengers. Additionally, melatonin reportedly neutralizes hydrogen peroxide, singlet oxygen, peroxynitrite anion, nitric oxide and hypochlorous acid. The following antioxidative enzymes are also stimulated by melatonin: superoxide dismutase, glutathione peroxidase and glutathione reductase. Melatonin has been widely used as a protective agent against a wide variety of processes and agents that damage tissues via free radical mechanisms.

/pdf/actions-of-melatonin-in-the-reduction-of-oxidative-stress-3jckeqdvi7.pdf

Actions of melatonin in the reduction of oxidative stress

Oxidative damage in the central nervous system: protection by melatonin.

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

https://repositorio.uca.edu.ar/bitstream/123456789/1653/1/melatonin-pleiotropic-orchestrating-regulator-molecule.pdf

Melatonin—A pleiotropic, orchestrating regulator molecule

Melatonin is widely abundant in many eukaryotic taxa, including vari-ous animal phyla, angiosperms, and unicells. In the bioluminescent dinoflagellate Gonyaulax polyedra, melatonin is produced in concentrations sometimes exceed-ing those found in the pineal gland, exhibits a circadian rhythm with a pro-nounced nocturnal maximum, and mimics the short-day response of asexual encystment. Even more efficient as a cyst inducer is 5-methoxytryptamine (5MT), which is also periodically formed in Gonyaulax. In this unicell, the photoperiodic signal-transduction pathway presumably involves melatonin formation, its deace-tylation to 5MT, 5MT-dependent transfer of protons from an acidic vacuole, and cytoplasmic acidification. According to this concept, we observe that cyst forma-tion can be induced by various monoamine oxidase inhibitors and protonophores, that 5MT dramatically stimulates H+-dependent bioluminescence and leads to a decrease of cytoplasmic pH, as shown by measurements of dicyanohydroquinone fluorescence. Cellular components from Gonyaulax catalyze the photooxidation of melatonin. Its property of being easily destroyed by light in the presence of cel-lular catalysts may have been the reason that many organisms have developed mechanisms utilizing this indoleamine as a mediator of darkness. Photooxidative reactions of melatonin, as studied with crude Gonyaulax extracts and, more in de-tail, with protoporphyrin IX as a catalyst, lead to the formation of N1 -acetyl-N -formyl-5-methoxykynuramine (AFMK) as one of the main products. Photochemical mechanisms involve interactions with a photooxidant cation radi-cal leading to the formation of a melatonyl cation radical, which subsequently combines with a superoxide anion. Photooxidation of melatonin represents one of several possibilities of a more general, biologically highly important property of this indoleamine to act as an extremely efficient radical scavenger, including its feature of terminating radical reaction chains by a final combination with the su-peroxide anion. Trapping of free radicals may reflect the primary and evolutionar-ily most ancient role of melatonin in living beings.

On the primary functions of melatonin in evolution: Mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals*

Mediation of photoperiodic effects by indoleamines, especially melatonin, is known in higher vertebrates. A similar mechanism may occur in a unicellular alga, the dinoflagellate Gonyaulax polyedra. This organism entered the dormant stage of a cyst upon short-day treatment at lowered temperatures. Interruption of darkness by 2 hours of light prevented cyst formation, even when the overall duration of light was the same as in cyst-inducing short days. When given in a noninducing photoperiod, melatonin and an analog, 5-methoxytryptamine, substances that had previously been shown to occur in Gonyaulax, provoked cyst formation. Methoxylated indoleamines may play a role as mediators of darkness in this unicellular, in a similar way as in vertebrates, suggesting a common biochemical basis of photoperiodism.

Photoperiodism and effects of indoleamines in a unicellular alga, Gonyaulax polyedra

Melatonin in Algae and Higher Plants - Possible New Roles as a Phytohormone and Antioxidant

Hemistasia phaeocysticola (Scherffel) comb. nov., Redescription of a Free-living, Marine, Phagotrophic Kinetoplastid Flagellate

Melatonin, a methoxylated indoleamine, plays a role as a mediator of darkness in animals as well as in the unicellular alga Gonyaulax polyedra Stein and was recently detected in higher plants. We report on the first finding of melatonin in a multicellular alga, the brown alga Pterygophora californica Rupr. Melatonin was identified in juvenile sporophytes of P. californica by two independent methods, reverse-phase high-performance liquid chromatography (HPLC) with electrochemical detection, and radioimmunoassay. Another indolic metabolite, 5-methoxytryptophol, was also indentified by HPLC. The rapid decline of growth rate upon the onset of darkness in P. californica is mimicked by melatonin in the light, with increasing efficiency from 5 × 10−5M to 5 × 10−4M, while no effect was obtained at 10−5M.

Ivonne Balzer

Papers

On the primary functions of melatonin in evolution: Mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals*

Photoperiodism and effects of indoleamines in a unicellular alga, Gonyaulax polyedra

Melatonin in Algae and Higher Plants - Possible New Roles as a Phytohormone and Antioxidant

Hemistasia phaeocysticola (Scherffel) comb. nov., Redescription of a Free-living, Marine, Phagotrophic Kinetoplastid Flagellate

The vertebrate pineal hormone melatonin is produced by the brown alga Pterygophora californica and mimics dark effects on growth rate in the light