A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C─C and C─N bonds

Guangzheng Wei, Borui Duan, Tai-Ping Zhou, Wenya Tian, Chenghai Sun, Zhi Lin, Zixin Deng, Binju Wang, Zhengyu Zhang, Xudong Qu

Proceedings of the National Academy of Sciences 2024

https://doi.org/10.1073/pnas.2412890121

Abstract

P450 peroxidase activity is rare and remains largely underexplored. This study reveals an exceptional P450 peroxidase system driven by nucleobases, which facilitates the synthesis of nucleobase-tryptophan-containing diketopiperazine (TDKP) dimers through a distinctive catalytic mechanism. Adenine and other modified 6-aminopurine nucleobases play dual roles as both substrates and acid–base catalysts in activating H2O2 through a refined substrate-residue hydrogen-bonding network, resulting in the formation of diverse nucleobase–TDKP dimers. These findings significantly advance our understanding of P450 peroxidase systems and the biosynthesis of nucleobase–TDKP dimers, underscoring the unique catalytic potential of nucleobases in enzymes. Moreover, they suggest promising avenues for developing P450 peroxidases and nucleobase-based biocatalysts.