Cyanobacterin biosynthesis opens up a new class of natural compounds for applications in medicine and agriculture

Researchers from the groups of Prof. Tobias Gulder from the Technical University of Dresden and Prof. Tanja Gulder from the University of Leipzig have succeeded in understanding the biosynthetic mechanisms for the production of the natural product cyanobacterin, which in nature is produced in small quantities by the cyanobacterium Scytonema hofmanni. In the process, they also discovered a new class of enzymes for building carbon-carbon bonds. (Bio)chemists thus significantly expand the currently known biocatalytic repertoire of Nature and open up new sustainable biotechnological applications in medicine and agriculture. The results of the collaboration have just been published in the journal Nature chemical biology.

The fact that Nature is an excellent chemist is demonstrated by the abundance of molecules, of so-called natural products, which it produces by biosynthesis. These natural products are also of great importance to us humans. They are used in myriad ways in our daily lives, including as active agents in medicine and agriculture. Prominent examples are antibiotics such as penicillins isolated from molds, the anti-cancer drug Taxol from Pacific yew and pyrethrins found in chrysanthemums, which are used to control pest infestations. 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 context, researchers from the groups of Prof. Tobias Gulder (TU Dresden) and Prof. Tanja Gulder (University of Leipzig) jointly investigated the biosynthesis of cyanobacterin, which is highly toxic to photosynthetic organisms and is produced in small amounts in nature by 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. Emphasis has been placed on how the central part of the carbon skeleton of cyanobacteria is produced. The putative genes for this were first cloned by the Direct Pathway Cloning (DiPaC) method and then activated in the model organism. E.coli as a cell factory. DiPaC is a new synthetic biology method previously developed in the lab of Tobias Gulder, professor of technical biochemistry at TU Dresden. “DiPaC allows us to very quickly and efficiently transfer complete biosynthetic pathways from natural products into recombinant host systems,” says Tobias Gulder. In the next step, the research team analyzed the essential individual steps of cyanobacterin biosynthesis by additionally producing all key enzymes in the host organism. E.coli, isolate them and then study the function of each enzyme. During this process, they came across a previously unknown class of enzymes called furanolide synthases. These are able to catalyze the formation of carbon-carbon bonds through an unusual mechanism. In other studies of these furanolide synthasesthese enzymes have proven to be effective in vitro biocatalysts, which makes them very attractive for biotechnology applications.

” With the furanolide synthaseswe have obtained an enzymatic tool that will allow us to develop more environmentally friendly methods for the production of bioactive compounds in the future and thus make significant contributions to more sustainable chemistry,” says Professor Tanja Gulder from the Institute of Organic Chemistry of the University of Leipzig Next, the two research teams want to specifically search for these new biocatalysts in other organisms as well, and thus find new bioactive members of this class of natural products, as well as develop methods of biotechnological production and structural diversification of cyanobacterin. “Our work paves the way for the full development of an exciting class of natural products for applications in medicine and agriculture,” agree the two scientists.

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Cyanobacterin biosynthesis opens up a new class of natural compounds for applications in medicine and agriculture

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