Creation and optimization of artificial metalloenzymes: Harnessing the power of directed evolution and beyond

Rising demands for efficient, selective, and versatile synthetic methods call for new enzymatic functions that may not be available in the biological realm. The challenges are daunting, requiring enzymes to take on new functions and requiring the newly developed biocatalysts to exhibit activity and selectivity comparable to or better than current chemocatalytic methods or fill gaps in synthetic chemistry. In this perspective, we summarize the current status of non-natural biocatalysis and describe how protein engineering, particularly directed evolution integrated with chemical rationalization, enables innovations that expand the chemical space accessible to enzymes. The creation of abiological enzymatic functions represents a growing area of research that requires knowledge from different fields, including protein engineering, enzymology, and synthetic chemistry.