Effect of pH on elementary steps of dopachrome conversion from first-principles calculation

Area of Science:

• Biochemistry
• Physical Chemistry
• Materials Science

Background:

• Eumelanin's antioxidant properties depend on the DHI/DHICA monomer ratio.
• Dopachrome conversion is a key step influencing this ratio.
• The underlying pH-dependent mechanism remains poorly understood.

Purpose of the Study:

• To elucidate the mechanism of dopachrome conversion to 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA).
• To understand how pH influences the DHI/DHICA ratio and conversion rate.
• To clarify the relationship between reaction kinetics and eumelanin's antioxidant activity.

Main Methods:

• First-principles calculations were employed to model dopachrome conversion.
• Analysis of proton rearrangement pathways and intermediate formation.
• Investigation of kinetic barriers for DHI and DHICA formation.

Main Results:

• Identified a kinetic preference for proton rearrangement to a quinone methide intermediate via β-deprotonation.
• Elucidated pathways for DHI formation through spontaneous decarboxylation after proton rearrangement.
• Demonstrated that α-deprotonation facilitates DHICA formation with a reduced activation barrier.
• Showed that proton rearrangement rates are pH-dependent.

Conclusions:

• The conversion of dopachrome to DHI and DHICA is mechanistically controlled by pH-dependent proton rearrangements.
• Acidic pH suppresses dopachrome conversion due to unfavorable proton rearrangement kinetics.
• Understanding these mechanisms is vital for controlling eumelanin's composition and antioxidant function.