**2. Melatonin synthesis**

Melatonin is synthesized from tryptophan in pinealocytes in the pineal gland. Synthesis stages are, respectively: Tryptophan is converted to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase. Then 5-hydroxytryptophan is converted to serotonin by the amino acid decarboxylase enzyme. Serotonin is converted to N-acetyl serotonin by the enzyme N-acetyl transferase. N-acetyl serotonin is converted to melatonin by the enzyme methyltransferase. Thus, the synthesized melatonin is released into the blood circulation [8, 9]. The regulation of melatonin synthesis is controlled by the retinohypothalamic pathway and a system that surrounds the suprachiasmatic nuclei and contains multiple synapses within this pathway. Stimuli from the retina reach the hypothalamus and then this information reaches the pineal gland via peripheral postganglionic sympathetic fibers and melatonin is synthesized [9]. It activates protein kinase C (PKC) via β- and α1-adrenergic receptors on pinealocytes with increased norepinephrine stimulation at night. PKC activation increases the Ca2+ movement in the cell, resulting in an increase in the concentration of intracellular cyclic adenosine monophosphate (cAMP). This increase activates protein kinase A (PKA) (**Figures 1** and **2**). Activated PKA increases AANAT activity [14]. Once synthesized, it is directly secreted into the cerebrospinal fluid and blood of the third ventricle and reaches all body tissues in a very short time. After melatonin is released, it is transported by diffusion and some carrier molecules [15]. Melatonin can regulate a variety of physiological functions, from the well-known modulation of sleep/wake cycles and circadian rhythms to the maintenance and regulation of neural development and immune system and endocrine functions [16]. These effects of the melatonin are mediated by G protein-linked melatonin receptors MT1 and MT2. In addition, activation of a putative cytoplasmic melatonin receptor MT3 is also effective [17]. When melatonin binds to these receptors, due to the connection between the

**Figure 1.** *Biosynthetic pathway of the melatonin.*

#### **Figure 2.**

*Synthesis of melatonin from tryptophan under the influence of light in the pineal gland [9]. SCG: Superior cervical ganglion; SCN: Suprachiasmatic nucleus; NA: Noradrenaline; PVN: Paraventricular nucleus; AADC: Aromatic-L-amino-acid decarboxylase AANAT: Arylalkylamine N-acetyltransferase, TPH: Hydroxytryptophan 5-hydroxylase. HIOMT: Hydroxy indole-O-methyltransferase NAS: N-asetlyserotonin.*

#### **Figure 3.**

*MT 1 and MT 2 melatonin receptor signaling. PKA, protein kinase a; cAMP response element-binding protein; MT, melatonin receptor; Akt, threonine protein kinase B (PKB; also known as Akt); cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CREB, IP3, inositol trisphosphate; MAPK, mitogenactivated protein kinase [18].*

receptors and Gai/o proteins, it causes activity in the target tissue by regulating the levels of cAMP and calcium, the second messenger, as well as by regulating the activation of PKC subtypes (**Figure 3**) [19]. As a result of various studies, it has been determined that these receptors of Melatonin are in various structures of the brain belonging to the nervous system [20] as well as in nonneural tissues such as the immune system, endocrine system, bone, gastrointestinal system, cardiovascular system and reproductive organs, which we will focus on [21]. Again, as a result of a study, it was determined that melatonin causes various activities in various tissues through a mechanism independent of its receptors [22].
