Structural basis of melanogenesis enzymes

Structural basis and molecular mechanisms of the human tyrosinase enzyme TYRP1 in melanogenesis

The production of the pigment melanin in mammals requires the activity of at least three melanogenic enzymes, tyrosinase (TYR) and tyrosinase-related proteins 1 (TYRP1) and 2 (TYRP2), which regulate the type and amount of melanin produced. Despite their essential role, the catalytic mechanism and specificity are still under strong debate.

The lack of structural data hampers the understanding of their molecular bases and the design of specific inhibitors to treat pigmentation disorders or melanoma1. We solved the crystal structure of human TYRP12,3, which challenges previous assumptions claiming it is a redox enzyme. In view of the existence of TYRP1 pathological mutations, it is thus very likely that TYRP1 plays a unique function in melanogenesis and different from TYR4.

This thesis projects aims to identify the TYRP1 pathway metabolites to unveil its function in the melanin biosynthesis pathway and to design efficient compounds to treat melanogenesis disorders. To this end, in partnership with the biotech company ImmuSmol, highly specific antibodies will be generated against potential TYRP1 substrates in order to profile their levels in TYRP1 knock out cells or containing disease-associated TYRP1 mutations.

Relevant metabolites will then be characterized with recombinant TYRP1 protein and the crystal structures of the enzyme-molecule complexes will be determined of in order to elucidate their catalytic activity and mode of action at the atomic level. Overall, this project will unveil the molecular function of TYRP1 in melanogenesis and will enable the design of specific anti-melanogenic compounds.