Research Interest
Genetic and Enzymatic Basis of Specialized Metabolism
We are fascinated by Nature's ability to craft specialized metabolites with spectacular molecular architectures. These genetically encoded and evolutionary optimized small molecules exhibit potent biological activities and equip human societies to combat infectious and immunological diseases, carcinosis or help to protect crops for the food supply.
We investigate the genetic and enzymatic basis of specialized metabolism with a focus on the discovery of novel enzymes and unprecedented chemistries in non-canonical natural product pathways. Therefore, we utilize an interdisciplinary methodological approach and combine state-of-the-art techniques from organic synthesis, mass spectrometry-guided metabolomics, genomics, bioinformatics, and enzymology in order to identify novel enzymes, investigate their mechanism on a molecular level and apply the obtained knowledge for biocatalyst development and genome-based natural product discovery.
With our work, we aim to contribute to two urgent research areas with wide environmental and societal concerns: a) the development of sustainable production platforms for the synthesis of pharmaceuticals and fine chemicals, and b) the discovery of novel lead structures for antiinfectives drug development.
Funded by:
Selected Publications from postdoctoral work:
Noncanonical Biosynthetic Pathways
Enzyme Cofactors as Building Blocks in Natural Product Biosynthesis
Enzymes involved in secondary metabolite biosynthetic pathways have typically evolutionarily diverged from their counterparts functioning in primary metabolism. They often catalyze diverse and complex chemical transformations and are thus a treasure trove for the discovery of unique enzyme-mediated chemistries. Besides major natural product classes, such as terpenoids, polyketides, and ribosomally or nonribosomally synthesized peptides, biosynthetic investigations of noncanonical natural product biosynthetic pathways often reveal functionally distinct enzyme chemistries. In this Perspective, we aim to highlight challenges and opportunities of biosynthetic investigations on noncanonical natural product pathways that utilize primary metabolites as building blocks, otherwise generally considered as enzyme cofactors. A focus is made on the discovered chemical and enzymological novelties.
Published in JACS Gold:
Discovery of a Novel Natural Product Class
β-NAD as a building block in natural product biosynthesis
β-Nicotinamide adenine dinucleotide (β-NAD) is a pivotal metabolite for all living organisms and functions as a diffusible electron acceptor and carrier in the catabolic arms of metabolism. Furthermore, β-NAD is involved in diverse epigenetic, immunological and stress-associated processes, where it is known to be sacrificially utilized as an ADP-ribosyl donor for protein and DNA modifications, or the generation of cell-signalling molecules. Here we report the function of β-NAD in secondary metabolite biosynthetic pathways, in which the nicotinamide dinucleotide framework is heavily decorated and serves as a building block for the assembly of a novel class of natural products. The gatekeeping enzyme of the discovered pathway (SbzP) catalyses a pyridoxal phosphate-dependent (3+2)-annulation reaction between β-NAD and S adenosylmethionine, generating a 6-azatetrahydroindane scaffold. Members of this novel family of β-NAD-tailoring enzymes are widely distributed in the bacterial kingdom and are encoded in diverse biosynthetic gene clusters. The findings of this work set the stage for the discovery and exploitation of β-NAD-derived natural products.
Published in Nature:
Utilizing Enzymes to Expand the Organic Synthetic Toolbox
Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids
Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.
Published in Angewandte Chemie: