The evolution of biocatalysis: From foundational enzymology to AI-guided biocatalysis through the legacy of Antonio Ballesteros

Abstract

Over nearly five decades, Antonio Ballesteros helped establish and consolidate biocatalysis at a time when catalysis research was dominated by inorganic chemistry. From early work on enzyme regulation and immobilization to later research on non-conventional media, semisynthetic enzyme stabilization, lipolytic and carbohydrate-active enzymes, metagenomic enzyme discovery and directed evolution, his scientific trajectory closely paralleled the maturation of biocatalysis from fundamental enzymology to an enabling technology for sustainable chemical processes. This commentary uses his career as a framework to trace the conceptual evolution of the field, from controlling individual enzymes to engineering integrated catalytic systems. Beyond specific technological advances, his lasting contribution lies in a platform-oriented vision that connected the enzyme itself, together with its stabilization and optimization, to process design within a coherent strategy. This integrative approach anticipated the current convergence of metagenomics, directed evolution and artificial intelligence (AI)-enabled exploration and the design of enzyme sequence spaces for biocatalysis. As biocatalysis has entered the era of data-driven design, machine learning and circular bioeconomy applications, many of the current challenges, such as navigating vast sequence space, predicting enzyme function, and engineering robust catalysts for industrial deployment, can be seen as extensions of principles he helped articulate decades ago. By revisiting key stages of his scientific trajectory, this commentary also highlights how the major research themes surrounding biocatalysis have evolved over time, from classical enzymology to metagenomic discovery, systems-level biocatalysis and AI-assisted enzyme design. His legacy therefore bridges the foundations of enzymology with the emerging AI-enabled future of biocatalysis.