The Mysterious World of Melanin
Melanin Science | The introduction of oxygen by photosynthetic bacteria 2.3 billion years ago induced adaptive changes to both harness and mitigate against aerobic oxidation.[1] Melanogenesis is one example that is conserved across the tree of life.[2] Humans pigment skin, hair and eyes with melanin, where it plays critical roles in vision, UV-protection, redox homeostasis and sexual attraction. A form of neuromelanin also exists in the brain, where it sequesters metal ions and reactive oxygen species.[3] Melanin is a dark, insoluble material that is bio-synthesized by aeorbic polymerization of L-tyrosine within an organelle called the melanosome. The shapes and sizes of melanosomes are tissue specific, and also vary from organism to organism, but are generally oblong or spherical, and hundreds to thousands of nanometers in length. The creation of melanin within the melanosome is a complex, multi-tiered process, which remains shrouded in mystery. The polymer is poorly soluble and irregular, and its extraction from the melanosome disrupts both its secondary structure, as well as its connectivity. How melanosomes control polymer production, and what structural features of the material lead to beneficial function remain unknown.
Natural and synthetic melanins can be produced as granules of varying size by aerobic oxidation of L-tyrosine. In most biological contexts, this is catlayzed by the enzyme tyrosinase, which is a dinuclear Cu-containing metalloenzyme. In the early 1900’s, studies by Raper and Mason identified DHICA and DHI as the downstream monomeric products of oxygenation. Because these heterocycles oxidize more easily than L-tyrosine, polymerization occurs spontaneously, and leads to poorly defined products of varied constitution.[2, 9] These, and related materials formed by aerobic polymerization of catechols, have a number of interesting mechanical and electronic properties. However, an inability to control both the connectivity and extent of polymerization leads to heterogeneous materials with broad polydispersities. It also prevents a rational means of improving material performance.
Melanogenesis | The aerobic polymerization of L-tyrosine catalyzed by the enzyme tyrosinase. The structure of melanin is unknown, and the poly-indole-catechol shown is only a representative drawing.
A Bottom-Up Approach | Our group is approaching the challenge of melanin science with a bottom-up synthetic strategy. By leveraging the precision of modern cross-coupling reactions, we can create well-defined melanin fragments with complete control over connectivity and length. This creates a means of producing well-defined melanin fragments with which we can study structure-function relationships. Our long-term vision is an automated synthesis platform for melanin materials, akin to protein or DNA synthesizers.
A Bio-Inspired Synthesis of Poly-Functional Indoles | Angew. Chemie. Int. Ed. 2018, 57, 11963-11967.
A Melanin Synthesizer | Our long term vision is a melanin synthesizer, akin to modern day peptide or DNA synthesizers.
RERERENCES
[1] Borden, W. T., Hoffmann, R., Stuyver, T. & Chen, B. Dioxygen: What Makes This Triplet Diradical Kinetically Persistent? J. Am. Chem. Soc. 139, 9010-9018, doi:10.1021/jacs.7b04232 (2017).
[2] d'Ischia, M. et al. Melanins and melanogenesis: from pigment cells to human health and technological applications. Pigment Cell & Melanoma Research 28, 520-544, doi:10.1111/pcmr.12393 (2015).
[3] Double, K. L., Maruyama, W., Naoi, M., Gerlach, M. & Riederer, P. in Melanins and Melanosomes 225-246 (Wiley-VCH Verlag GmbH & Co. KGaA, 2011).
[4] García-Borrón, J. C. & Olivares Sánchez, M. C. in Melanins and Melanosomes 87-116 (Wiley-VCH Verlag GmbH & Co. KGaA, 2011).
[5] Functions, P. (eds Jan Borovanský & Patrick A. Riley) (Wiley-VCH Verlag GmbH & Co. KGaA, 2011).
[6] Rolff, M., Schottenheim, J., Decker, H. & Tuczek, F. Copper-O(2) reactivity of tyrosinase models towards external monophenolic substrates: molecular mechanism and comparison with the enzyme. Chem. Soc. Rev. 40, 4077-4098, doi:10.1039/c0cs00202j (2011).
[7] Solomon, E. I. et al. Copper Active Sites in Biology. Chem. Rev. 114, 3659-3853, doi:10.1021/cr400327t (2014).
[8] Ito, S., Wakamatsu, K., d'ischia, M., Napolitano, A. & Pezzella, A. in Melanins and Melanosomes 167-185 (Wiley-VCH Verlag GmbH & Co. KGaA, 2011).
[9] d'Ischia, M., Napolitano, A. & Pezzella, A. 5,6-Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin. European Journal of Organic Chemistry 2011, 5501-5516, doi:10.1002/ejoc.201100796 (2011).