Biocatalytic Heteroaromatic Amide Formation in Water Enabled by a Catalytic Tetrad and Two Access Tunnels

Authors

Erna Zukic, M.Sc. (acib GmbH ), Dániel Mokos (Universität Graz), Melanie Weber (Universität Graz), Niklas Stix (Universität Graz), Prof. Dr. Klaus Ditrich (BASF SE), Valerio Ferrario (University of the study of Trieste), Henrik Müller (BASF SE), Dr. Christian Willrodt (BASF SE), Univ.-Prof. Mag. Dr.rer.nat. Karl Gruber (Universität Graz), Dr.techn. Bastian DANIEL, BSc. MSc. (Universität Graz) and Prof. Dr. Wolfgang Kroutil (Universität Graz)

Scientists have found a smart, eco-friendly way to make amides, which are essential building blocks for many medicines. Usually, making amides requires harsh chemicals and solvents that create waste. This new method uses a natural catalyst, an enzyme called SpL, which works efficiently in just water.
Researchers tested many enzymes and found SpL, originally from Sphingomonas bacteria, to be particularly effective. It can take complex starting materials (heteroaromatic esters) and combine them with various amines to form the desired amides. The reactions happen quickly in simple buffer solution at mild temperatures, sometimes in just minutes, and produce high yields of the final product, often up to 99%. Impressively, the enzyme manages this even though water itself could interfere with the reaction.
What makes SpL special? Detailed studies revealed it has a unique structure. Besides the usual active parts, it has an extra helper component (an aspartate residue) that prepares the amine to react. It also features two separate tunnels leading to its core, one for each starting material. This prevents the molecules from getting in each other’s way and allows the enzyme to handle even bulky starting materials.
This breakthrough offers a much greener and more efficient way to produce important chemical compounds. It reduces waste, avoids toxic solvents, and simplifies the manufacturing process. This could significantly benefit the pharmaceutical industry by providing a sustainable route to producing existing drugs and developing new ones, making chemical synthesis cleaner and more efficient.