Melanins and melanogenesis: what can we learn from chemical studies?

Because of the notorious difficulties in the direct investigations of natural melanins, it has become customary over the past decades to gain structural and biochemical information through model studies carried out on putative precursors and intermediates. In consequence, current studies rely mostly on a bottom-up approach aimed at reconstructing the biosynthetic process of pigment buildup. By this approach, it has been possible to delineate novel mechanisms of eumelanin oligomer formation from 5,6-dihydroxyindoles and to identify some elusive quinonoid intermediates that have challenged previous workers. Likewise, considerable advances in the field of pheomelanin formation via benzothiazine and benzothiazole intermediates seem to be just behind the door. Overall, the knowledge that has rapidly accumulated over the past few years has led to an entirely new appreciation of the chemical bases underlying certain critical features and properties of melanins relating to their functional significance. However, despite the unquestionable potential of the chemical approach, as integrated by computational methodologies, an issue remains of how far this reductionist approach can go in unraveling the many intricacies of melanin research. The main gap lies in the difficulty to mimic and handle in a test tube the complex biological environment in which natural pigments are produced, whereby it is becoming clearer that failure to duly consider these differences may engender misleading conclusions. This presentation aims at providing an overview of the latest advances in the structural investigation of eumelanins and pheomelanins as emerging from ongoing studies in our laboratory. It also seeks to show how the new information can be properly used, in the attempt to bridge the gaps between the properties of synthetic pigments and the biological features of natural eumelanins and pheomelanins.