The biosynthesis and enzymology of complex rubromycin and tropone marine bacterial natural products

• Applicant: Professor Dr. Robin Teufel
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439507043

Marine natural products remained a largely untapped and underexplored source of pharmaceutically interesting compounds for a long time. Meanwhile, numerous bioactive marine natural products have been characterized, many of which derive from bacteria. Often, these molecules feature highly intricate structures that impede or completely thwart chemical synthesis, while their biosynthesis depends on unusual enzyme reactions. My research project focusses on the detailed characterization of the enzymology underlying the biosynthesis of ecologically and pharmaceutically interesting natural products that, e.g., serve as defensive tools for marine invertebrates (corals, tunicates, oysters, or sponges), as exemplified by tropone-based natural products such as tropodithietic acid or rosebacticides. These compounds are produced, e.g., by predominant marine bacteria such as Roseobacter or coral-associated Pseudovibrio sp., where they serve as potent coral protectants, algaecides, or bacterial signaling molecules. In the past, we elucidated the bacterial phenylacetic acid catabolic pathway and identified the postulated precursor for tropone natural products. We now aim to acquire all enzymes required for the biosynthesis of thee metabolites and characterize them in detail to enable the in vitro enzymatic synthesis of these natural products and gain insight into the underlying biochemistry. As a second pillar of the project, the biosynthesis of the rubromycin family of aromatic polyketides will be investigated that are produced by Actinobacteria, which are commonly isolated from marine tunicates. Until recently, little details were known about the biosynthesis of rubromycins, in particular of the spiroketal pharmacophore that is exceptional among aromatic polyketides and essential for their potent bioactivities. We successfully reconstituted the complete enzymatic spiroketal pharamacophore formation in vitro that granted insight into novel enzyme reactions and led to the discovery of various previously unrecognized intermediates. We now seek to solve the structures of these enzymes and conduct detailed mechanistic studies to further our understanding of these complex biosynthetic steps. Moreover, final pathway steps that modify the spiroketal will be investigated. Taken together, both project parts aim at elucidating the enzymology underlying the biosyntheses of ecologically and pharmaceutically relevant marine natural products. This knowledge may be useful, e.g., for the establishment of in vivo and in vitro production platforms and bioengineering of bioactive compounds, while also furthering our fundamental understanding of how structural complexity is generated in nature.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partner: Professor Dr. Jörn Piel