Tracking the melanogenic pathway to unravel the functional role of melanins: the bottom-up approach

Investigation of the structural features of melanins, both the dark eumelanins and the reddish brown variants pheomelanins, has ever represented a formidable challenge because of the minute amounts occurring in the natural sources, the molecular heterogeneity, the low solubility in water and other solvents, and the susceptibility to (photo)oxidation. These difficulties have hampered an insight into the structure-property-function relationships of crucial relevance to the biological role of the pigments, particularly in humans, including skin (photo) protection and UV-susceptibility. Investigation of the biosynthetic pathway has represented a most rewarding approach pursued since the pioneering studies by Raper.1 This led to the identification of 5,6-dihydroxyindoles as the ultimate precursors of eumelanins, whereas the discovery of the intervention of cysteine onto dopaquinone highlighted cysteinyldopas, as precursors of pheomelanins, and later benzothiazines as their oxidation products.2 An amazing similarity of the eumelanin and pheomelanin pathways is decarboxylation at critical branching points, namely the rearrangement of dopachrome to 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and of 5-S-cysteinyldopa o-quinoneimine to 1,4-benzothiazine (BTZ) and its 3-carboxylic acid (BTZCA). In eumelanins, the DHICA-to-DHI ratio markedly affects the antioxidant and paramagnetic properties of the resulting pigments. In particular, a higher content in DHICA decreases visible light absorption and paramagnetic response relative to DHI-based melanins, but markedly enhances antioxidant properties. In pheomelanins, likewise, BTZCA-related units appear to confer pronounced visible and UVA absorption features, accounting for light-dependent reactive oxygen species (ROS) production, whereas non-carboxylated benzothiazine intermediates seem to be more effective in inducing ROS production by redox cycling mechanisms in the dark.3,4 This presentation will illustrate how this bottom-up approach has led to significant insights into the complex structural features of either eumelanins or pheomelanins, and to a better understanding of their functional role, providing also the rational for the exploitation of model pigments obtained from the biosynthetic precursors in the biomedical and dermocosmetic field.