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Identification and characterisation of natural products from fungal non-reducing NRPS-like enzymes


School of Life Sciences

About the Project

Project Overview:
Fungi are a treasure chest of yet unexplored natural products. As only a minor fraction of the full potential of natural product biosynthesis of fungi has been explored, it can be assumed that a vast number of metabolites with interesting pharmaceutical and biotechnological properties is still to be discovered. In this respect, non-reducing NRPS-like enzymes are a class of natural product forming enzymes that are frequently found in fungal genomes, but only a few enzymes and corresponding metabolites have been characterised so far. Nevertheless, biological activities of the few metabolites show an importance in stress protection, nutrition, quorum sensing and phytotoxicity.

The project aims in the heterologous expression of fungal non-reducing NRPS-like enzymes with and without co-expression of modifying enzymes from biosynthesis gene clusters followed by analysis of metabolite products and determination of biological activities. The project will mainly be based in the Fungal Biology groups of the University of Nottingham but will also involve collaborations with other groups from Engineering and the Centre for Biomolecular Science at the University of Nottingham as well as collaboration partners in Germany. This ensures that all techniques and equipment required for the successful characterisation of natural products are available.
The project will provide training in the identification of secondary metabolite biosynthesis gene clusters from fungal genomes and will have a focus on molecular biology techniques to amplify and clone selected genes in expression plasmids for heterologous expression in fungal expression platform strains. Selected strains will be grown under conditions that induce metabolite production followed by metabolite extraction and analytical techniques for structure elucidation. Furthermore, protein purification will allow in vitro production of secondary metabolites to characterise protein function in a cell-free system. Finally, NRPS-like enzymes and tailoring enzymes from different biosynthesis gene clusters will be combined to generate novel-to-nature secondary metabolites.

The PhD student working on this project will receive a detailed training in fungal cultivation and microbiology techniques, molecular biology, genetic modification of microorganisms and natural product isolation and characterisation. A basic knowledge in biochemistry, molecular biology and working with fungi is strongly recommended.

References

1) Geib E, Baldeweg F, Doerfer M, Nett M, Brock M (2019) Cross-Chemistry leads to product diversity from atromentin synthetases in aspergilli from section Nigri. Cell Chem Biol. 26: 223-234
2) Geib E, Brock M (2017) ATNT: an enhanced system for expression of polycistronic secondary metabolite gene clusters in Aspergillus niger. Fung. Biol. Biotechnol. 4:13l
3) Gressler M, Hortschansky P, Geib E, Brock M (2015) A new high-performance heterologous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front Microbiol 6, 184

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