White Biotechnology: New Step for Antibiotics

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Biochemists and organic chemists from Freie Universität Berlin along with partners are working on biotechnological production of bioactive molecules / Cooperation with TU Munich and Bar-Ilan University in Israel

No 253/2018 from Sep 28, 2018

Scientists at Freie Universität Berlin, together with research teams from Munich and Israel, have unraveled the reaction mechanism of a biotechnologically relevant enzyme. Based on the new findings, it is possible to generate a wide variety of, and in some cases, novel, complex biologically effective molecules. Since the enzyme can be incorporated into microorganisms in a biological production cascade, compound production using this method is resource saving and environmentally friendly. The method, which falls into the category of "white biotechnology," thus represents an alternative to classical organic synthesis. Dr. Bernhard Loll and his research team at the Institute of Chemistry and Biochemistry, Freie Universität Berlin, were able to show that understanding the enzymatic reaction at the atomic level is fundamental to the novel design of the binding site of the enzyme. With these findings the scientists at Freie Universität Berlin, TU Munich, and Bar-Ilan University hope first and foremost for new insights into the mechanism of the enzyme and, in the long term, the possibility of introducing even more targeted modifications into the enzyme.

Terpenes are the largest group of natural products with currently more than 60,000 known compounds. Due to their diverse properties, they are used in almost all areas of industry, for example, as fragrances, pharmaceuticals, insecticides, or as biofuel. Thus, the structural diversity of this class ranges from simple acyclic fragrances such as citronella to monocyclic terpenes, which include menthol, to complex polycyclic terpenes such as the anti-tumor drug Taxol (paclitaxel). However, the highly complex polycycles with multiple stereocenters are difficult to access with classical organic synthesis. An alternative is the production of terpenes in modified microorganisms: all components required for the synthesis are integrated into microorganisms. Terpene synthases take over the cyclization of the linear starting molecule, thus functioning as a central building block.

Currently, classical organic synthesis is based on chemical precursors that can be produced from petroleum. Numerous synthesis steps are performed at high temperature and pressure. The production of bioactive compounds in microorganisms on an industrial scale is therefore a highly interesting alternative. On the one hand, the use of fossil resources is minimized, and on the other hand, production is environmentally friendly. In this work, Dr. Bernhard Loll and his research team demonstrate the use of an enzyme (CotB2), which seems extremely interesting for the production of various bioactive molecules. For example, these new molecules show anti-inflammatory or antibacterial properties. The insights gained are an important step in understanding how nature engineered these enzymes.

The scientists working together on this research, Ronja Driller from Dr. Bernhard Loll’s group, Prof. Mathias Christmann and his group at Freie Universität Berlin, Professor Thomas Brück at TU Munich, and Professor Dan Thomas Major at Bar-Ilan University in Israel, investigated the so-called diterpene synthase CotB2, a biotechnologically relevant enzyme. They successfully brought a variety of expertise in biochemistry, organic chemistry, biotechnology, and computer-based simulations into the project. The results provide profound insights into the mechanism of this enzyme.

Based on these results, it seems that in the future it will be possible to generate tailor-made terpene synthases to synthesize compounds with the goal of using them, for example, in the fight against cancer or as a new class of antibiotics.


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