Mechanism of dopachrome tautomerization into 5,6-dihydroxyindole-2-carboxylic acid catalyzed by Cu(II) based on quantum chemical calculations.

BACKGROUND

Tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) is a biologically crucial reaction relevant to melanin synthesis, cellular antioxidation, and cross-talk among epidermal cells. Since dopachrome spontaneously converts into 5,6-dihydroxyindole (DHI) via decarboxylation without any enzymes at physiologically usual pH, the mechanism of how tautomerization to DHICA occurs in physiological system is a subject of intense debate. A previous work has found that Cu(II) is an important factor to catalyze the tautomerization of dopachrome to DHICA. However, the effect of Cu(II) on the tautomerization has not been clarified at the atomic level.

METHODS

We propose the reaction mechanism of the tautomerization to DHICA by Cu(II) from density functional theory-based calculation.

RESULTS

We clarified that the activation barriers of α-deprotonation, β-deprotonation, and decarboxylation from dopachrome are significantly reduced by coordination of Cu(II) to quinonoid oxygens (5,6-oxygens) of dopachrome, with the lowest activation barrier of β-deprotonation among them. In contrast to our previous work, in which β-deprotonation and quinonoid protonation (O5/O6-protonation) were shown to be important to form DHI, our results show that the Cu(II) coordination to quinonoid oxygens inhibits the quinonoid protonation, leading to the preference of proton rearrangement from β-carbon to carboxylate group but not to the quinonoid oxygens.

CONCLUSION

Integrating these results, we conclude that dopachrome tautomerization first proceeds via proton rearrangement from β-carbon to carboxylate group and subsequently undergoes α-deprotonation to form DHICA.

GENERAL SIGNIFICANCE

This study would provide the biochemical basis of DHICA metabolism and the generalized view of dopachrome conversion which is important to understand melanogenesis.