Biochemistry and Antioxidant Effects of Melatonin

*Oguz Merhan*

### **Abstract**

Melatonin (N-acetyl-5-methoxy-tryptamine) is a hormone taking place in many biological and physiological processes, such as reproduction, sleep, antioxidant effect, and circadian rhythm (biological clock), and is a multifunctional indolamine compound synthesized mainly from the metabolism of tryptophan via serotonin in the pineal gland. Melatonin, which is a hormone synthesized from the essential amino acid tryptophan, is substantially secreted from the pineal gland between the cerebral hemispheres found in the mammalian brain. In addition to this, it is also produced in the cells and tissues, such as the gastrointestinal system, gall, epithelial hair follicles, skin, retina, spleen, testis, salivary glands, bone marrow, leukocytes, placenta, and thrombocytes. It plays a role in many physiological events, such as synchronizing circadian rhythms, reproduction, fattening, molting, hibernation, and change of pigment granules, preserving the integrity of the gastrointestinal system with an antiulcerative effect in tissues and organs from which it is produced. Melatonin is also a powerful antioxidant and anti-apoptotic agent that prevents oxidative and nitrosative damage to all macromolecules due to its ability to form in metabolic activities, directly excrete toxic oxygen derivatives, and reduce the formation of reactive oxygen and nitrogen species. In this book chapter, we will explain the structure, synthesis, metabolism, and antioxidant effects of the melatonin hormone.

**Keywords:** antioxidant, biochemistry, melatonin, shikimate pathway, tryptophan

#### **1. Introduction**

Melatonin (N-acetyl-5-methoxy-tryptamine) is a hormone taking place in many biological and physiological processes and is a multifunctional indolamine compound synthesized mainly from the metabolism of tryptophan via serotonin in the pineal gland [1]. Its molecular formula is C13H16N2O2 and its molecular weight is 232.278 g/mol (**Figure 1**) [2]. It has the capacity to be able to pass through all biological membranes due to its small molecular size and high lipophilicity and it is evenly distributed to all biological tissues and fluids by crossing the blood–brain barrier [3].

Although the existence of the pineal gland has been known since ancient times, the French philosopher Rene Descartes described the pineal gland as the "throne of the soul" about three hundred years ago [4]. Melatonin hormone was first described in 1958 by the American dermatologist Aaron Lerner by obtaining from the pineal gland of cattle [5]. Melatonin, which is produced in the cells called pinealocytes of

**Figure 1.** *Chemical structure of melatonin.*

the pineal gland, is a hormone that plays a role in the regulation of many physiological and biological functions, such as circadian rhythm, sleep/wake cycle, pubertal development-reproduction, locomotor activity, regulation of immunity and blood pressure, molting, and hibernation [6–10].

Cortisol and melatonin levels act in opposite directions. Immediately after cortisol levels drop at night, melatonin levels begin to increase. The balance between these two hormones is important for good health and various diseases can occur with low melatonin and high cortisol levels [11, 12].

While melatonin shows a stimulating effect on the gonads in animals, such as sheep, goats, and deer, it shows suppressive properties in animals, such as horses, hamsters, and camels [13]. Melatonin acts as a timer by providing to follow-up the changes in the light/dark ratio of the animal seasonally [14].

In sheep, melatonin secretion and plasma levels are low in daylight [15, 16]. After sunset, melatonin secretion increases 10–20 times and rises rapidly to reach a peak by the end of the night. Thus, melatonin signal reflects the duration of the dark phase [14]. Melatonin initiates a series of events that lead to the start of the reproduction season [17]. The decreasing light exposure time increases melatonin secretion in the autumn-winter months when the days start to get shorter. Increased melatonin secretion stimulates gonadotrophin-releasing hormone (GnRH) secretion and provides to initiate estrus by acting on the hypothalamus in sheep [18, 19].

### **2. Melatonin**

#### **2.1 Tryptophan synthesis**

The shikimate pathway is found in bacteria, fungi, plants, and algae, as well as in some protozoans. However, this pathway does not occur in animals and therefore animals must obtain aromatic amino acids from their diets as essential nutrients. Phosphoenolpyruvate (PEP), sugar with 3-carbon, product of the glycolysis pathway and erythrose-4-phosphate (E4-P), sugar with 4-carbon, synthesized from the pentose phosphate pathway starts with its conversion to

*Biochemistry and Antioxidant Effects of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.106260*

2-keto-3-deoxy-D-arabinoheptulosonate 7-phosphate, 7-carbon compound, with the hydrolysis of phosphate by 2-keto-3-deoxy-D-arabino-heptulosonate 7-phosphate synthase enzyme [20, 21].

In the second reaction, 3-dehydroquinate, a cyclic product, occurs by elimination of phosphate from 2-keto-3-deoxy-D-arabinoheptulosonate 7-phosphate by the catalysis of 3-dehydroquinate synthase enzyme with the help of NAD+ . 3-dehydroshikimate is formed from this product with the effect of 3-dehydroquinate dehydratase enzyme as a result of the loss of the H2O molecule [20, 22].

The next reaction is the reduction of 3-dehydroshikimate to shikimate by the shikimate dehydrogenase enzyme, which is used as a cofactor with NADPH. It is converted to shikimate 3-phosphate by the shikimate kinase enzyme by using one ATP per molecule. 5-enolpyruvylshikimate-3-phosphate is formed from shikimate 3-phosphate by binding to phosphoenolpyruvate (PEP) and catalyzing with 5-enolpyruvylshikimate-3-phosphate synthase enzyme. In the last reaction, 5-enolpyruvylshikimate-3-phosphate is converted to chorismate by the enzyme chorismate synthase [21, 23].

It forms anthranilate from chorismate formed in the last reaction of the shikimate pathway by giving amino group, which is part of the indole ring, in subsequent reactions for glutamine amino acid by way of the anthranilate synthase enzyme, which catalyzes the initial reaction of tryptophan biosynthesis [22]. N-(5′-phosphoribosyl) anthranilate is formed as a result of the elimination of pyrophosphate from phosphoribosyl-pyrophosphate (PRPP) by the enzyme anthranilate phosphoribosyltransferase. N-(5′-phosphoribosyl) anthranilate isomerase is responsible for the isomerization of N-(5′-phosphoribosyl) anthranilate to enol-1-o-carboxyphenylamino-1-deoxyribulose phosphate [24, 25].

Indole-3-glycerol-phosphate synthase catalyzes its conversion to indole-3-glycerol-phosphate by decarboxylating enol-1-o-carboxyphenylamino-1-deoxy-ribulose phosphate. In the last reaction, tryptophan synthase catalyzes the formation of tryptophan from indole-3-glycerol-phosphate by using indole and serine amino acids (**Figure 2**) [21, 26].

#### **2.2 Synthesis of melatonin**

*Anabolism*: Tryptophan is a nonpolar amino acid containing an indole ring [27]. Tryptophan amino acid, which is in the class of essential amino acids, is required to be taken from the diet through nutrition since it cannot be synthesized in humans and monogastric animals [20].

Melatonin, which is synthesized from the amino acid tryptophan, is synthesized in bacteria, unicellular eukaryotes, and plants. Melatonin is synthesized from retina, gastrointestinal system, kidney, liver, thyroid gland, bone marrow, leukocytes, membranous cochlea, placenta, Harderian gland, gonads, breast tissue, adrenal gland, lung, skin, adipose tissue, blood vessels, lymphocytes, neutrophils, lymphoid tissues, and some brain areas, is mainly synthesized from the pineal gland [28, 29].

The pineal gland plays an important role as a functional neuroendocrine transducer of photoperiodic changes that occur in environmental or seasonal events by activating N-acetyl transferase transfer [30]. Norepinephrine is the most important transmitter in the postganglionic sympathetic nerve endings in this gland. The suprachiasmatic nucleus (SCN), which is one of the nuclei that can receive signals from the retina through nerves during the day and in light, effectively inhibits the release of norepinephrine from these nerve endings [31, 32]. In the dark, the release

of norepinephrine from the nerve endings begins. Norepinephrine then binds to β-adrenergic receptors on the pinealocyte membrane and causes an increase in intracellular cAMP. As a result, it increases the activity of the N-acetyltransferase enzyme, which is a rate-limiting enzyme in melatonin synthesis in increasing intracellular cAMP and melatonin synthesis increases from serotonin [30, 32].

*Biochemistry and Antioxidant Effects of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.106260*

Melatonin synthesis begins with the uptake of tryptophan from the circulatory system by pinealocytes [33]. While tryptophan is converted to 5-hydroxytryptophan by the tryptophan hydroxylase enzyme catalysis, 5-hydroxy-tryptophan is also converted to serotonin (5-hydroxy-tryptamine) via aromatic L-amino acid decarboxylase [34]. N-acetyl serotonin is formed with the catalysis of 5-hydroxytryptamine N-acetyltransferase enzyme. N-acetyl serotonin is converted into melatonin (N-acetyl-5-methoxy-tryptamine) by being methylated with the catalysis of 5-hydroxyindole-o-methyltransferase enzyme (**Figure 3**) [28, 35, 36].

*Catabolism***:** Melatonin is metabolized by isoforms of cytochrome P450 monooxygenase enzymes (CYP1A2, CYP1A1, and CYP1B1) found in the liver. Of these isoforms, both CYP1A2 and CY2C19 enzymes can demethylate melatonin to N-acetyl serotonin or can convert melatonin to 6-hydroxymelatonin by hydroxylation [37]. The half-life of melatonin, of which 70% is transported to the liver depending on albumin, varies between 3 and 45 minutes [38]. Less than 1% of melatonin is reported to be excreted with urine as 6-sulphatoxymelatonin by conjugating lesser extent with glucuronic acid or mostly conjugating with sulfate for the rest (**Figure 3**) [39, 40].

**Figure 3.** *Anabolism and catabolism of melatonin.*
