Abstract
Biocatalysis is currently undergoing a profound transformation. The field moves from relying on nature's chemical logic to a discipline that exploits generic activation modes, allowing for novel biocatalytic reactions and, in many instances, entirely new chemistry. Generic activation modes enable a wide range of reaction types and played a pivotal role in advancing the fields of organo- and photocatalysis. This perspective aims to summarize the principal activation modes harnessed in enzymes to develop new biocatalysts. Although extensively researched in the past, the highlighted activation modes, when applied within enzyme active sites, facilitate chemical transformations that have largely eluded efficient and selective catalysis. This advance is attributed to multiple tunable interactions in the substrate binding pocket that precisely control competing reaction pathways and transition states. We will highlight cases of new synthetic methodologies achieved by engineered enzymes and will provide insights into potential future developments in this rapidly evolving field.