In this manuscript we have attempted to provide a systematic examination of these properties with a particular emphasis on how they modulate cytotoxic processes of both melanin and pathways influenced by melanin. These additional properties have been incorporated into natural defenses and also have been a potential source of pathophysiology. While some of the functions of melanin, especially protection against damage from light, have evolved by natural selection, other functions seem to have arisen from the myriad physical–chemical properties intrinsic to melanin, especially interactions with metal ions and related oxidation/reduction reactions. A mechanism of dopachrome tautomerization into DHICA catalyzed by Cu(II), based on quantum chemical calculations, indicated the important role of Cu(II) coordination to the oxygen of quinoids of dopachrome. Indeed, it was shown that Cu(II) ions stimulated the rearrangement of dopachrome to DHICA. Interestingly, the interaction of metal ions with melanin precursors could affect the result of melanogenesis. Although dopachrome, one of the main intermediates of melanogenesis, spontaneously converts to DHI, the biosynthesis of eumelanin pigments involves enzymatic tautomerization of dopachrome to DHICA, which significantly increases the percentage of DHICA monomers in natural eumelanin. Key monomer units of the eumelanin oligomers are 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), as well as their oxidized forms. So-called eumelanin is the main naturally occurring mammalian melanin pigment, responsible for brown–black coloration of pigmented tissues. Basic building blocks of melanin are nanoaggregates of relatively small oligomers formed not only via enzymatic process but also spontaneously from the reactions of active precursors, such as dopaquinone. Melanin is widely present in most or all complex animals. While the value of EPR spectroscopy and other EPR-related techniques for the study of melanin is emphasized, the concomitant use of other physicochemical methods is the most efficient approach. The paper reviews basic physicochemical properties of melanin responsible for binding of metal ions and discusses specific conditions that may induce cytotoxicity of metal ions such as iron and copper by facilitating their redox activation and release from melanin. In the latter function, sequestration of redox-active metal ions and scavenging of reactive oxygen species are of importance. Although the main biological function of melanin is protection against damage from solar radiation, melanin may also be involved in protection against oxidative stress. The formed melanin granule consists of nanoaggregates of oligomers containing different monomers. In humans, specialized cells called melanocytes synthesize the pigment from tyrosine and 3,4-dihydroxyphenylalanine via enzyme-catalyzed reactions and spontaneous processes. Many pharmacologically active substances are able to inhibit or stimulate melanin biosynthesis, as evidenced by in vitro studies on cultured pigment cells.Melanin is one the most common biological pigments. Activity of the key melanogenic enzyme, tyrosinase, is also affected by pH and temperature.

The article presents the intracellular signaling pathways: cAMP/PKA/CREB/MITF cascade, MAP kinases cascade, PLC/DAG/PKCβ cascade and NO/cGMP/PKG cascade, which are involved in the regulation of expression and activity of the melanogenesis-related proteins by ultraviolet radiation and endogenous agents (cytokines, hormones). Regulation of melanogenesis is achieved by physical and biochemical factors. Eumelanin is formed by polymerization of DHI and DHICA and their quinones. In the absence of thiol compounds DOPAquinone undergoes an intramolecular cyclization and oxidation to form DOPAchrome, which is then converted to 5,6-dihydroksyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA). The addition of cysteine or glutathione to DOPAquinone leads to the intermediates formation, followed by subsequent transformations and polymerization to the final product, pheomelanin. Melanogenesis is a multistep process and begins with the conversion of amino acid L-tyrosine to DOPAquinone. Biosynthesis of melanins takes place in melanosomes, which are specialized cytoplasmic organelles of melanocytes - dendritic cells located in the basal layer of the epidermis, uveal tract of the eye, hair follicles, as well as in the inner ear, central nervous system and heart. Melanins are natural pigments of skin, hair and eyes and can be classified into two main types: brown to black eumelanin and yellow to reddish-brown pheomelanin.

Tyrosine melanin dopamine drawit