Protein Modifications: From Chemoselective Probes to Novel Biocatalysts

Abstract

Chemical reactions can be performed to covalently modify specific residues in proteins. When applied to native enzymes, these chemical modifications can greatly expand the available set of building blocks for the development of biocatalysts. Nucleophilic canonical amino acid sidechains are the most readily accessible targets for such endeavors. A rich history of attempts to design enhanced or novel enzymes, from various protein scaffolds, has paved the way for a rapidly developing field with growing scientific, industrial, and biomedical applications. A major challenge is to devise reactions that are compatible with native proteins and can selectively modify specific residues. Cysteine, lysine, N-terminus, and carboxylate residues comprise the most widespread naturally occurring targets for enzyme modifications. In this review, chemical methods for selective modification of enzymes will be discussed, alongside with examples of reported applications. We aim to highlight the potential of such strategies to enhance enzyme function and create novel semisynthetic biocatalysts, as well as provide a perspective in a fast-evolving topic.