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Journal Article

Enzyme-Directed Mutasynthesis: A Combined Experimental and Theoretical Approach to Substrate Recognition of a Polyketide Synthase

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons101523

Bravo-Rodriguez,  Kenny
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons101503

Sanchez-Garcia,  Elsa
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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cb300505w_si_001-1.pdf
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Citation

Sundermann, U., Bravo-Rodriguez, K., Klopries, S., Kushnir, S., Gomez, H., Sanchez-Garcia, E., et al. (2013). Enzyme-Directed Mutasynthesis: A Combined Experimental and Theoretical Approach to Substrate Recognition of a Polyketide Synthase. ACS Chemical Biology, 8(2), 443-450. doi:10.1021/cb300505w.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-C923-D
Abstract
Acyltransferase domains control the extender unit recognition in Polyketide Synthases (PKS) and thereby the side-chain diversity of the resulting natural products. The enzyme engineering strategy presented here allows the alteration of the acyltransferase substrate profile to enable an engineered biosynthesis of natural product derivatives through the incorporation of a synthetic malonic acid thioester. Experimental sequence−function correlations combined with computational modeling revealed the origins of substrate recognition in these PKS domains and enabled a targeted mutagenesis. We show how a single point mutation was able to direct the incorporation of a malonic acid building block with a non-native functional group into erythromycin. This approach, introduced here as enzyme-directed mutasynthesis, opens a new field of possibilities beyond the state of the art for the combination of organic chemistry and biosynthesis toward natural product analogues.