Nature-Inspired Enzymatic Cascades: Emerging Strategies for Sustainable Chemistry

Enzymatic cascades, defined here as multi-enzymatic sequences operating on a shared reaction pathway and inspired by the spatial and temporal organization of metabolism, have emerged as powerful and versatile tools for sustainable organic synthesis. They minimize intermediate isolation, enhance atom economy and ensure outstanding chemo-, regio- and stereoselectivity, providing efficient alternatives to conventional multistep routes. Here, we highlight the conceptual role of substrate channeling, minimal cells, artificial metabolism and enzyme promiscuity in the translation of enzymatic cascades into synthetic strategies. Special attention is focused on advanced immobilization on functional and renewable supports, which enhance stability and recyclability and introduce new ways for thermodynamic and kinetic control. Hybrid systems integrating enzymes with photocatalysis, electrochemistry and chemical modules expand the catalytic repertoire far beyond biology. Complementary tools in bioinformatics, structural modeling and artificial intelligence may also enable pathway balancing, predictive design and dynamic optimization. Applications span from the valorization of renewable feedstocks to the synthesis of privileged scaffolds and fine chemicals.