When biocatalysis meets flow chemistry

Introduction
The fast evolution of enzyme engineering during the last decade has dramatically impacted the number of industrial processes that involve one or more biocatalytic steps for the preparation of fine chemicals including pharmaceuticals, cosmetics, agrochemicals and bioactive compounds (1). Among the most impressive examples in the pharmaceutical sector, the enzymatic total synthesis of Islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI) for HIV infection, has been achieved by Merck in 2019 (2). Nine enzymes, most of which had to be carefully engineered, were required for the accomplishment of such a synthesis, with four of those biocatalysts serving exclusively as ancillary systems for cofactor recycling or equilibrium shifting. Another inspiring example regards the heavily engineered transaminase ATA 117 employed as a key catalyst to replace a rhodium-mediated asymmetric enamine hydrogenation step for the preparation of the blockbuster drug Sitagliptin (3). Additionally, starting from tropical berries a particular protein has been prepared by Amai Proteins company. Due to its sweetening power (3000 times sweeter than sugar), it has the potential to replace the commonly used sweeteners without health hazards and off-flavors, dramatically impacting the food sector (4).

What is clear is that protein preparation is no longer a problem, and the concern about biocatalysis as an expensive niche technology, incompatible with the majority of industrial processes has been dismantled. Especially, with the progress of enzyme engineering, which included Prof. Frances Arnold among the Nobel laureates, precise design of enzymes became possible, transforming biocatalysis in a smart strategy to be employed for industrial needs. In a parallel way, a special attention has been paid to highly-performing enzyme-mediated reactions, shifting the technical set-up from batch mode to alternative solutions. Among them, the combination of catalyst stabilization and reutilization via enzyme immobilization and flow chemistry facilities, represents a leap forward in increasing the sustainability, safety and productivity of biotransformations, eventually impacting on process efficiency and relative costs (5-7).