Noncanonical Amino Acids in the Design of Artificial Metalloenzymes

In nature, some of the most challenging reactions require metalloenzymes. While natural metalloenzymes catalyze diverse reactions, the type of catalysis is limited by the combination of chemical functional groups present on canonical amino acids and natural metal ions/cofactors. To overcome this, an innovative approach is to design artificial metalloenzymes, which may lead to unlocking new-to-nature biocatalysis. The genetic code expansion is a useful tool that facilitates the design of new artificial metalloenzymes. Introducing noncanonical amino acids into proteins facilitates the design of novel metal-binding sites and fine-tunes the chemical properties of the primary and secondary coordination spheres. This chapter provides an overview of the various strategies employed to design artificial metalloenzymes using noncanonical amino acids, discussing their opportunities and challenges. Furthermore, the biocatalytic applications of multiple artificial metalloenzymes containing noncanonical amino acids for diverse new-to-nature reactions are discussed.