Learning from nature: Cyanobacterin biosynthesis opens new class of natural compounds for applications in medicine and agriculture

image: Fermentation of cyanobacteria in a photobioreactor at the TU Dresden
vision Lake

Credit: Prof. dr. Tobias Gulder

That nature is an excellent chemist is shown by the abundance of molecules, so-called natural products, which she produces biosynthetically. These natural products are also of crucial importance to us humans. They are used in many ways in our daily life, especially as active substances in medicine and agriculture. Prominent examples are antibiotics such as penicilins isolated from fungi, the anticancer agent taxol from the Pacific yew tree, and pyrethrins found in chrysanthemums, which are used to control pests. The knowledge and understanding of the biosynthetic assembly of such compounds by nature is essential for the development and production of drugs based on such compounds. In this regard, researchers from the groups of Prof. Dr. Tobias Gulder (TU Dresden) and Prof. Tanja Gulder (University of Leipzig) jointly promote the biosynthesis of cyanobacterin, which is highly toxic to photosynthetic organisms and is produced in small quantities in nature by the cyanobacterium Scytonema Hofmanni† In their work, the (bio)chemists were not only able to elucidate the biosynthesis of the natural product for the first time, but also discovered a new enzymatic transformation for the formation of carbon-carbon bonds.

This work was made possible by combining modern tools from bioinformatics, synthetic biology, enzymology and (bio)chemical analysis. The focus was on how the central part of the cyanobacterin carbon skeleton is produced. The putative genes for this were first cloned by the method of “Direct Pathway Cloning” (DiPaC) and then activated in the model organism E coli as a cell factory. DiPaC is a new synthetic biological method that was previously developed in the laboratory of Tobias Gulder, professor of Technical Biochemistry at the TU Dresden. “DiPaC allows us to very quickly and efficiently transfer entire biosynthetic pathways from natural products to recombinant host systems,” explains Tobias Gulder. In the next step, the research team analyzed the essential individual steps of cyanobacterin biosynthesis by additionally producing all major enzymes in the host organism E coli, isolating them and then investigating the function of each enzyme. In the process, they encountered a previously unknown class of enzymes called furanolide synthases† These are able to catalyze the formation of carbon-carbon bonds by an unusual mechanism. In further studies of this furanolide synthasesthese enzymes were found to be efficient in vitro biocatalysts, making them very attractive for biotech applications.

“With the furanolide synthaseswe have obtained an enzymatic tool that will allow us in the future to develop more environmentally friendly methods for the production of bioactive substances and thus make an important contribution to a more sustainable chemistry,” explains Prof. Tanja Gulder from the Institute of Organic Chemistry at University of Leipzig. The two research teams want to specifically search for these new biocatalysts in other organisms, finding new bioactive members of this class of natural products, as well as developing methods for the biotechnological production and structural diversification of cyanobacterin. “Our work paves the way for the comprehensive development of an exciting class of natural products for applications in medicine and agriculture,” the two scientists agree.

Original publication:

Paul M. D’Agostino, Catharina J. Seel, Xiaoqi Ji, Tanja Gulder and Tobias AM Gulder. Cyanobacterin biosynthesis, a paradigm for the assembly of the furanolide core structure. Nature Chemical BiologyDOI: https://doi.org/10.1038/s41589-022-01013-7
Read-only version: https://rdcu.be/cOoe7

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