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Uncovering New Fungal Secondary Metabolites and Biosynthetic Pathways Using “Omics” Technologies
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Uncovering New Fungal Secondary Metabolites and Biosynthetic Pathways Using “Omics” Technologies
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Dissertation
Uncovering New Fungal Secondary Metabolites and Biosynthetic Pathways Using “Omics” Technologies
2020
Overview
Natural products from fungi have had an immeasurable societal impact as both friends and foes to human health. This includes numerous therapeutics that have had widespread clinical success, mycotoxins that are implicated in fungal pathogenicity, and various agrochemicals. Recent genome sequencing efforts have revealed that fungal genomes contain the capacity to produce an enormous wealth of natural products, representing a significant resource for future compound discovery. Given this vast wealth of new natural products, high-throughput approaches are needed for systematically accessing the compounds encoded by fungal genomes. Traditional natural products discovery approaches are decidedly low-throughput and operate in an information-poor fashion that leads to rediscovery of known compounds and diminishing returns. Alternative approaches that take full advantage of recent advances in “omics” technologies such as genomics and metabolomics are needed for tackling the vast number of fungal compounds and biosynthetic pathways that awaits discovery. In order to meet this challenge, integrative approaches were developed that combine large-scale metabolomics and genomics for joint discovery of new compounds and their biosynthetic pathways. A heterologous expression approach was developed and implemented that expresses entire fungal biosynthetic gene clusters, enabling compound identification by mass spectrometry-based metabolomics. This platform was used to study two unusual biosynthetic pathways with peculiar metabolite scaffolds: terreazepine, a kynurenine-derived benzazepine metabolite, and acu-dioxomorpholine, a diketomorpholine metabolite formed by a non-canonical peptide synthetase. Large-scale genome mining for new natural products requires informatics tools for cataloguing, visualizing, and navigating this chemical space. A web resource based on 1000 fungal genomes was created to meet this need. With this resource in hand, a large-scale analysis of biosynthetic pathways in the fungal kingdom was performed, revealing the relationship between secondary metabolism and phylogeny. This work provides a roadmap and tool for systematically accessing new natural products from fungal genomes.
