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Switzerland Project Notice - Biosynthesis, Enzymology And Biotechnology Of Bacterial Aromatic Polyketide And Tropone Natural Products


Project Notice

PNR 54351
Project Name Biosynthesis, Enzymology and Biotechnology of Bacterial Aromatic Polyketide and Tropone Natural Products
Project Detail Background and rationale: Natural products and their derivatives remain among the most important sources for novel drug leads. Many of these compounds are structurally complex, which makes synthetic strategies cumbersome or even unfeasible; therefore, biological and/or biotechnological approaches are often required to procure them. However, the underlying enzymology is often poorly understood and involves unconventional chemistry, thus rendering the detailed investigation of the biosynthetic strategies and pathways challenging. Consequently, extensive genetic and biochemical studies are typically required to gain a basic understanding of the biosynthetic strategies. This is exemplified by the bioactive bacterial aromatic polyketide and tropone natural products, whose intricate biosyntheses are only partially understood. These compounds act for instance as antimicrobials, protein inhibitors or toxins and often play important roles in mutualistic and antagonistic symbiotic interactions in the marine and terrestrial environment. Accordingly, some represent potential lead compounds for drug development, while others are being investigated for industrial applications, e.g., as protective antibiotics in (shell)fish aquaculture. Overall objectives, specific aims and methods: In this proposal, I seek to elucidate crucial missing steps in the biosynthesis of aromatic polyketides of the rubromyin and angucyclin family as well as of tropone natural products with a focus on oxygen-and sulfur incorporating enzymes and their regulation. The involved key enzymes will be studies in greater detail on a structural and mechanistic level. To achieve that, X-ray crystallography will be applied in conjunction with biochemical (e.g., site-directed mutagenesis & enzyme kinetics) and computational investigation of the enzymes as well as the detailed analysis of the formed intermediates and final products (e.g., via ultra-high performance liquid chromatography mass spectrometry (UPLC-MS) and nuclear magnetic resonance (NMR) spectroscopy) combined with isotope labelling). For the tropones, identified hallmark enzymes will furthermore serve as a handle to identify novel putative biosynthetic gene clusters via data base searches (e.g., BlastP, MultiGeneBlast etc.), which should enable the discovery of novel producer strains and tropone natural products. The respective bacteria will then be obtained and investigated for the formation of tropones, which will be identified by UPLC-MS, MS networking combined with database-assisted dereplication and NMR spectroscopy. Finally, the knowledge obtained from these studies will serves as a prerequisite for rational enzyme design and biotechnological approaches to enable the formation of novel natural product derivatives. Expected results and impact: These studies will unravel missing steps and non-canonical tailoring reactions in the biosynthesis of polyketide and tropone natural products. The structural and mechanistic insights gained from studying these key enzymes will furthermore broaden our understanding of how such biocatalysts mediate regio- and chemoselective oxygen and sulfur transfer reactions and control ensuing carbon backbone rearrangement to ultimately form the pharmacophores of bioactive natural products. This knowledge will not only expand our current understanding of the enzymology underlying the biosynthesis of ecologically and pharmaceutically important natural products, but also provide the basis to exploit and optimize these enzymes for biotechnological applications and the generation of bioactive “unnatural” natural products.
Funded By Self-Funded
Sector
Country Switzerland , Western Europe
Project Value CHF 1,013,925

Contact Information

Company Name University of Basel - BS
Web Site https://data.snf.ch/grants/grant/212747

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