Natural Product Biotechnology

The biosynthesis of natural products in organisms is catalyzed by enzymes. In the genomes of microbial natural product producers, these enzymes are usually encoded in so-called Biosynthetic Gene Clusters (BGCs). This allows biosynthetic pathways to be efficiently discovered through modern bioinformatic analyses. To harness the natural product molecules they encode, we utilize production in heterologous host systems. For this, interesting BGCs are transferred from natural producers into efficient microbial production systems through the development and application of cloning methods. One example is our recently developed Direct Pathway Cloning (DiPaC) approach. This method enables the direct amplification of interesting BGCs using PCR and their transfer into overexpression vectors. The expression construct is fully assembled in vitro, allowing full flexibility regarding the expression vectors used and bypassing potential issues with product toxicity during cloning. DiPaC also allows for the restructuring of biosynthetic pathways directly during the cloning process. For example, this enables the manipulation of regulatory processes to optimize production, as well as the deletion or exchange of pathway-specific genes to elucidate biosynthetic mechanisms (see below).

During the course of evolution, Nature developed an enormous diversity of functionally distinct enzymes that efficiently enable the biosynthesis of complex natural product structural frameworks. To utilize these biocatalysts in drug research, it is essential to understand their molecular mechanisms in detail. Therefore, our department works on elucidating the individual functions of biosynthesis enzymes and their interplay in natural product biosynthesis. On the one hand, the functions and application potentials of biosynthetic genes in BGCs of interesting natural products are studied by their deletion and exchange in vivo. This also allows for the targeted expansion of natural structural and functional diversity through molecular biology and biotechnological approaches. On the other hand, we produce promising enzymes through heterologous expression and decipher their functions and substrate tolerance through detailed in vitro characterization. This forms the basis for their application in efficient chemo-enzymatic synthetic approaches (see below).

The complexity of the structures of natural products has challenged the creativity of synthetic organic chemists for decades. The goal of synthesizing such compounds in the laboratory has led to the development of a wealth of innovative synthetic methods and elegant reaction pathways. However, in many cases, the developed arsenal of chemical reactions is not sufficient for the efficient production of larger quantities of natural products or for comprehensive structure-activity relationship studies. The optimization of synthetic pathways through the integration of enzymatic key steps has the potential to sustainably solve these problems. In our department, we are particularly interested in the application of enzymes that enable the rapid construction of molecular complexity, thus making natural products efficiently and selectively accessible. Examples of this work include the synthetic and chemo-enzymatic production of sorbicillinoid natural products, polycyclic tetramate macrolactams, antibiotic myxocoumarins, ambigols, and peptides, as well as heterocyclic building blocks for use in medicinal chemistry.