Biocatalytic Synthesis of Challenging Macrocycles

Organic synthesis can be seen as the art and science of replicating the molecules of living nature and creating others like them in the laboratory (K.C. Nicolaou). However, even after more than a century of research and method development, the production of some organic molecules in the laboratory is still challenging. Macrocycles, i.e., large ring-shaped molecules, are examples of molecules that bear a manifold of biological and pharmaceutically interesting activities and that are found in nature in a broad diversity. However, as the methods to obtain these rings are inefficient, rely on toxic chemicals and are very unpredictive, such molecules cannot be broadly evaluated for their potential as active pharmaceutical ingredients in medicinal chemistry, and only a very limited number of such molecules are currently marketed as pharmaceuticals. Still, the interest in investigating the bioactivities of such structures in medicinal chemistry is high, as the biological activities of the macrocycles that are found in nature are often outstanding. For this reason, the FWF project Biocatalytic Synthesis of Challenging Macrocycles aims to establish new methods to synthetize such challenging molecules. However, instead of further developing the current artificial synthetic methods, the project will investigate those processes that Nature applies for the synthesis of its own portfolio of macrocyclic molecules. For this purpose, enzymes form the class of thioesterases, which are Nature`s ring formation tools, will be identified, characterized and applied for the production of both, natural and artificial large ring-shaped molecules. A team of organic chemists and molecular biologists (Christoph Winker and Wolfgang Kroutil, University of Graz) as well as medicinal chemists, structural biologists and computational chemists (Pedro Alejandro Snchez Murcia, Medical University of Graz) will join forces to realize this goal. Within the project this team aims to: - Understand the reactivity and selectivity of thioesterases - Establish thioesterases as a tool for organic synthesis - Use further enzymes to allow the direct use of readily available carboxylic acids as starting material - Gain a deeper understanding of the mechanism and function of thioesterases - Apply the identified thioesterases for the synthesis of valuable macrocycles of medicinal interest