Artificial metalloenzymes

The development of artificial metalloenzymes (ArMs) aims to expand the capabilities of enzymatic catalysis, most notably towards new reaction mechanisms. Frequently, ArMs harness metal cofactors that are not naturally found in enzymes and embed these in specifically selected or designed protein scaffolds. ArMs have been developed for a wide range of natural and non-natural reactions, underscoring their potential to revolutionize fields such as biocatalysis or metabolic engineering. At the same time, replicating the catalytic prowess of natural enzymes is a highly challenging task, and several limitations need to be overcome to make ArM catalysis widely applicable. In this Primer, we introduce the state of the art in designing and engineering ArMs, describing best practices and important examples and achievements. Moreover, we consider potential applications of ArMs, as well as outstanding challenges, and discuss how these may be addressed in the coming years. Artificial metalloenzymes harness metal cofactors that are not naturally found in enzymes and embed these in specifically selected or designed protein scaffolds. In this Primer, Vornholt et al. describe the best practices for designing and engineering artificial metalloenzymes.