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Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the -SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys-S - ) to DQ. Interestingly, the C2-S bonded intermediate was less energetically stable than the C6-S bonded case. Furthermore, the most preferred Cys-S - -attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3-C4 bridge site) but not on the C5 site. This structure allows the Cys-S - to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5-S (and C2-S) intermediate into 5- S -cysteinyldopa (and 2- S -cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys-S - to DQ proceeds via the following path: (i) coordination of Cys-S - to C3-C4 bridge, (ii) migration of Cys-S - to C5 (C2), (iii) proton rearrangement from cysteinyl -NH 3  + to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4).

Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone