Enzymes are highly efficient biocatalysts known for their chemical, regio-, and stereoselectivity, making them valuable in industrial applications. While directed evolution has expanded the scope of enzyme-catalyzed reactions, the range of enzymatic reactions remains limited compared to reactions catalyzed by chemical catalysts. Computational enzyme design has achieved de novo enzyme design, but the approach is often complex, time-intensive, and has a low success rate. A promising strategy to design novel enzymes involves developing noncanonical amino acids (ncAAs) with catalytic potential and integrating them into protein scaffolds via genetic codon expansion technology. This method combines the novel reactivity of ncAAs with the high selectivity provided by protein scaffolds, significantly enhancing the diversity of enzyme-catalyzed reactions. This review discusses recent advancements in novel enzyme design using ncAAs, including those being used as catalytic groups, metal-coordinating groups, heme ligands, and photocatalytic groups. The article emphasizes the broad potential of using ncAAs in enzyme design to expand the diversity of enzyme-catalyzed reactions, and outlooks the potential applications of artificial intelligence technology in this area.
Cheng et al. (Mon,) studied this question.