Home Career Discovery of biochemical “rings of power” – ScienceDaily

Discovery of biochemical “rings of power” – ScienceDaily

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Benzobactins are bacterial natural products that have special biological activity due to a compound consisting of two ring structures. The bacterial genes responsible for the formation of the compound were previously unclear. Scientists at the Max Planck Institute for Terrestrial Microbiology have now been able to decipher its biosynthesis using extensive genomic studies. Their research facilitates the discovery of many previously unknown natural compounds for medical therapy.

In their natural habitat, microorganisms are often exposed to changing environmental conditions that require multiple survival responses. Most effective is their ability to produce a wide range of natural products with different chemical structures and functions.

Benzobactins are powerful but rare

Benzaxazolinate is a rare natural compound that provides extraordinary biological activity to natural products. It is, for example, an essential part of lidomycin, an anticancer antibiotic that is one of the most cytotoxic compounds to date. The reason for this ability is that benzoxazolinate consists of two rings, a structure that allows it to interact with protein as well as DNA. However, the search for producers of this rare substance in nature resembles the proverbial search for a needle in a haystack.

In order to exploit new pharmaceutically valuable natural compounds, such as antibiotics, tumor suppressors or immunosuppressants, it is necessary to know the responsible genes, or rather their biosynthetic gene clusters (BGCs). BGCs are locally clustered groups of two or more genes that together encode the production of a specific set of enzymes – and thus the corresponding natural products produced by those enzymes.

Until now, the biosynthetic gene cassette of benzoxazolinate has remained elusive, which has hindered the expansion of the repertoire of biologically active compounds containing benzoxazolinate. More specifically, the last step in the formation of benzoxazolinate was unclear. Now, a group of Max-Planck scientists led by Dr. Yi-Ming Shi and Prof. Dr. Helge Bode have succeeded in the biosynthetic characterization of the benzoxazolinate pathway. During biosynthesis, this pathway apparently “borrows” an intermediate of the so-called phenazine pathway, which is responsible for the production of another natural product. Most importantly, the researchers identified the enzyme responsible for the final step, the cyclization to benzoxazolinate.

Using an enzyme as a probe for natural substances

PhD student Jan Kremes, one of the authors of the study, which was also funded by the LOEWE Center for Translational Genomics of Biodiversity (LOEWE TBG) and the European Research Council, explains: “Knowing the identity of the enzyme, we used it as a probe. Through genome analysis, we were able to identify many closely related pathways biosynthesis of natural products containing benzoxazolinate, the so-called benzobactins.” According to the scientists, the most striking aspect was the widespread distribution of these genes in other bacteria. “These pathways were found in taxonomically and ecologically diverse bacteria, ranging from land to ocean, as well as in plant pathogens and biocontrol microorganisms. Their widespread distribution indicates that these molecules have a significant ecological function for growers,” said Yi-Min Shi, first author of the study.

Professor Helge Bode, head of the Natural Products in Organism Interactions at the Max Planck Institute for Terrestrial Microbiology in Marburg, adds: “Our results show the enormous biosynthetic potential of the widespread benzobactin biosynthetic gene cluster. Now we have to find out their ecological function and whether we can use them as antibiotics or other drugs.”

Crystallization and structural analysis of the key enzyme was carried out in collaboration with Dr. Laura Chesch and Prof. Gert Bang from SYNMIKRO, Phillips University Marburg. Enzyme kinetics were analyzed by Nicole Pazio and team at our Core Center for Metabolomics and Small Molecule Mass Spectrometry. Genome sequencing was carried out by Professor Jorn Kalinowski and a team from the University of Bielefeld.

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Materials is provided Max Planck Society. Note: Content can be edited for style and length.

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