“The field of organic chemistry is not exhausted”: Baeyer–Villiger Monooxygenases as a Tunable Biocatalyst

Despite the indispensable role they play in modern society, the pharmaceutical and chemical industries often find themselves contending with a less-than-favorable public image, primarily due to concerns surrounding pollution, accidents, and misinformation. Yet, the advent of “Green Chemistry” offers a glimmer of hope for addressing these challenges by not only minimizing environmental impact but also enhancing the efficiency of production processes. Green chemistry is an emerging branch of chemistry that adheres to the principle of "atom economy." It focuses on how to fully utilize starting materials and energy during the process of producing target products, while minimizing the release of harmful substances. The aim of green chemistry is to maximize reaction efficiency, minimize waste, and reduce environmental harm to the lowest extent possible. Throughout the entire process, from raw materials to the final product, green chemistry seeks to decrease waste generation and reduce various adverse impacts on the environment, such as pollution or other forms of environmental degradation¹.

One classical example that encapsulates this potential for improvement is the Baeyer-Villiger reaction, an established procedure for the oxidation of ketones to esters. While it's a convenient route for chemical synthesis, its widespread application has been hindered by the necessity of employing hazardous chemical reagents and bad selectivity in some cases². Over several decades, scientific research has been exploring the utility of biocatalysts, specifically flavin-containing Baeyer-Villiger monooxygenases (BVMOs), as a safer and more sustainable alternative for performing this oxidation. A range of BVMO variants have been rigorously studied and characterized, shedding light on their promising capabilities.

In this upcoming seminar, I will traverse a comprehensive landscape that includes the historical applications, structural attributes, and catalytic mechanisms of BVMOs. As we journey through this scientific territory, we'll delve deep into the molecular intricacies of these fascinating enzymes^3-4. Then modify or design new enzymes that can fulfill the need of current industry and laboratory. Special attention will be devoted to contemporary advancements in enzyme engineering—covering the tailoring of BVMOs for specific industrial applications. Our focus will be not only on cataloging what has been achieved thus far but also on critically examining the steps being taken to make these enzymes more amenable to large-scale industrial applications⁵. From mutation strategies that improve enzyme stability to co-factor recycling techniques that enhance operational efficiency, we'll explore the multi-faceted efforts underway to move BVMOs from laboratory settings to industrial production lines.

1 Fürst, M. J., Gran-Scheuch, A., Aalbers, F. S., & Fraaije, M. W. (2019). Baeyer–Villiger monooxygenases: tunable oxidative biocatalysts. ACS Catalysis, 9(12), 11207-11241.

2 ten Brink, G.-J. .; Arends, I. W. C. E.; Sheldon, R. A. The Baeyer−Villiger Reaction: New Developments toward Greener Procedures. Chemical Reviews 2004, 104 (9), 4105–4124. https://doi.org/10.1021/cr030011l.

3 Chánique, A. M.; Polidori, N.; Lucija Sovic; Kracher, D.; Leen Assil-Companioni; Galuska, P.; Parra, L. P.; Gruber, K.; Kourist, R. A Cold-Active Flavin-Dependent Monooxygenase from Janthinobacterium Svalbardensis Unlocks Applications of Baeyer–Villiger Monooxygenases at Low Temperature. ACS Catalysis 2023, 13 (6), 3549–3562. https://doi.org/10.1021/acscatal.2c05160.

4 Wang, J.; Li, G.; Reetz, M. T. Enzymatic Site-Selectivity Enabled by Structure-Guided Directed Evolution. Chemical Communications 2017, 53 (28), 3916–3928. https://doi.org/10.1039/c7cc00368d.

5 Zhang, Y.; Wu, Y.; Xu, N.; Zhao, Q.; Yu, H.-L.; Xu, J.-H. Engineering of Cyclohexanone Monooxygenase for the Enantioselective Synthesis of (S)-Omeprazole. ACS Sustainable Chemistry & Engineering 2019, 7 (7), 7218–7226. https://doi.org/10.1021/acssuschemeng.9b00224.