Combinatorial Biosynthesis of Fungal Meroterpenoid Assembly Lines

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The scientific goal of the research project is the utilization of fungal meroterpenoid biosynthetic machineries to generate novel molecular structures with potentially new or improved biological properties by a combinatorial biosynthetic approach.Meroterpenoids belong to a structurally diverse group of hybrid secondary metabolites with pharmaceutically relevant features. Known members of this group and synthetic derivatives thereof are clinically used as immunosuppressant drugs or have been developed as commercial insecticides. Other known meroterpenoids contain structural motifs, which are promising drug leads and are currently investigated for the treatment of atherosclerosis or neurodegenerative diseases like Morbus Alzheimer. Besides chemical synthetic approaches, the combinatorial biosynthesis method is a unique tool to generate novel or altered molecular structures and makes use of the systematic manipulation of metabolic pathways by recombination of different biosynthetic genes. The genetic basis to apply this method to meroterpenoids has only recently been discovered and the rational and controlled recombination of meroterpenoid pathways to create second-generation molecules is the focus of this research project. Specifically, the potential of key enzymes, the recently discovered family of meroterpenoid cyclases, to catalyze formation of new molecular scaffolds will be exploited. For that purpose, their substrate promiscuity will be investigated in detail and based on the obtained results, artificial biosynthetic pathways will be designed and reconstituted in a heterologous host. By this method an efficient production of the new "unnatural" natural products can be achieved and the biological activity of the obtained compounds will be investigated.The results from this research project can potentially contribute to improve human health by obtaining new drug candidates or drug lead structures. At the same time, the in-depth knowledge about the enzymatic basis of meroterpenoid biosynthesis will contribute to future advances to engineer and evolve their catalytic activities to meet human or ecological purposes.