Research groupsKalesse group
Research - Evolutionary analysis

Research - Evolutionary analysis

© Daniel Lohrberg/LUH
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Based on our capabilities to make structure predictions form analyzing keto-reductases and being able to generate all polyketides at will, we started a program to synthesize natural products based on the predicted structure and not on the observed structure. With this, we try to get insight into how microorganisms optimize the biological activity of natural products for their needs.

In this context, we synthesized and evaluated the biological properties of the iso-tedanolide and paleo-soraphen.  

By generating a different lactone, tedanolide is able to bind to two targets in the translation process whereas iso-tedanolide binds only to one cellular target. Thus the biosynthetically not expected transesterification lead to a more potent cytotoxic compound.

The same research idea was applied to soraphen. By analyzing the biosynthesis clusters, we realized that the expected structure differs significantly from the isolated structure. By synthesizing the putative product and analyzing their biological activities we observed a completely different biological behavior. The natural soraphen is a bacterial acetyl-CoA carboxylase inhibitor whereas paleo-soraphen parallels the activity of a topoisomerase inhibitor. This indicates that microorganisms may also change the addressed target through significant structural changes of the natural products. Again, we are expecting even more insight in how microorganisms use natural products to address cellular targets and the power of synthesis is the essential tool to answer these biological questions.