The expanded landscape of metalloproteins by genetic incorporation of noncanonical amino acids

Proteins are versatile macromolecules whose sequence space and chemical scope can be expanded infinitely. A chemical toolbox other than the 20 canonical amino acids can further diversify protein structure and function. Indeed, genetic code expansion to incorporate noncanonical amino acids (ncAAs) has extensively flourished metalloproteins in various aspects. This review focuses on artificial metalloproteins and metalloenzymes built using ncAAs, which operate directly as metal‐ligating ligands, modulate the chemical properties of metallocofactors within unique secondary coordinating microenvironments, or provide unique functions. As a result, self‐assembled protein architectures or novel catalytic activities have been created, showing the expanded landscape of metalloproteins. We also discuss potential prospects for ncAAs and their future applications in the design of protein‐based biomaterials and biocatalysts. Noncanonical amino acids became a versatile chemical toolbox for creating coordinate covalent bonds between proteins and metal ions or fine‐tuning pre‐existing inorganic reactivities of metallocofactors. Thus, artificial metalloproteins and metalloenzymes have been built by genetically incorporating noncanonical amino acids, resulting in novel protein structures and functions.