Melatonin target proteins: interactions and functions

Melatonin (N-acetyl-5-methoxytryptamine) is the primary hormone of the pineal gland. However its synthesis also occurs in various extra-pineal tissues, including brain, retina, retinal pigment epithelium, gastrointestinal tract, bone marrow, thymus, lymphocytes, and skin. Melatonin is an amphiphilic indole derivative that combines hydrophilic (methyl and amide groups) and hydrophobic (indole core) molecular domains. Due to its unique structure, which ensures high bioavailability, and presence of hormone and enzymatic mechanisms for its synthesis in various organs and tissues, melatonin is involved in regulating numerous physiological processes, thus highlighting its significant role in maintaining systemic homeostasis. The pleiotropic effects of melatonin are due to a combination of its direct molecular interactions and mediated regulatory mechanisms. On the one hand, melatonin is a powerful endogenous antioxidant capable of directly neutralizing reactive oxygen and nitrogen species. On the other hand, its physiological effects are realized through binding to specific protein targets, as well as via secondary mechanisms, including activation of antioxidant defense, metabolic, and epigenetic modulation. Interaction of this hormone with numerous extracellular and intracellular molecular targets is of particular interest, with binding affinity varying across a wide range of concentrations. Numerous studies over recent decades have identified about twenty distinct protein targets of melatonin, spanning a broad spectrum of functional categories – from well-characterized receptors (both membrane-bound and nuclear) to some non-canonical targets. The latter include: enzymes (quinone reductase-2, matrix metalloproteinase-9, protein phosphatase-2A, pepsin), ion channels, transport and structural proteins (glucose transporter GLUT1, oligopeptide transporters PEPT1 and PEPT2, serum albumin, tubulin), calcium-binding proteins (calmodulin, protein kinase C, calreticulin). Recently, the search for melatonin targets is continued. It is suggested that, in addition to its mediated effects, the hormone may directly modulate activity of P-glycoprotein, a membrane drug resistance protein and NAD+-dependent deacetylases – sirtuins SIRT1 and SIRT3. Studying the melatonin targets is crucial for analyzing its pharmacodynamic effects. A search for new targets opens perspectives for understanding its non-circadian functions of this hormone, e.g., neuroprotection, anticancer effects, and metabolic modulation.