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An enzyme module that generates an unusual type of polyketide natural product has been found. The discovery could help further diversify combinatorial biosynthesis to create novel natural-product-like molecules for drug discovery and other applications. Polyketide synthases are enzyme systems that take simple precursor molecules and string them together to form polymeric products, such as the fungus-produced antimitotic and antitumor agent rhizoxin. Although polyketide synthase-produced molecular backbones often fold over to produce macrocyclic final products, polyketide synthase modules generally create linear backbones. Now, a module that fuses a ring onto an extending linear chain has been uncovered. The work was carried out by Georg Zocher of Eberhard Karls University, in Tübingen, Germany; Christian Hertweck of Leibniz Institute for Natural Product Research & Infection Biology, in Jena, Germany; and coworkers (Nature 2013, DOI: 10.1038/nature12588). “This behavior imparts a second dimension to biosynthesis catalyzed by these giant enzymes and potentially provides synthetic biologists with a tool to modify and rigidify polyketide synthase products in a predictable manner,” notes Craig A. Townsend of Johns Hopkins University in a Nature commentary.
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