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

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.

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Sundermann, Uschi1, 2, Author
Bravo-Rodriguez, Kenny3, Author              
Klopries, Stephan1, Author
Kushnir, Susanna1, Author              
Gomez, Hansel4, Author
Sanchez-Garcia, Elsa3, Author              
Schulz, Frank1, 2, Author
Affiliations:
1Fakultät für Chemie, Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Str. 6, 44221 Dortmund, Germany, ou_persistent22              
2Max-Planck-Institut für molekulare Physiologie, Abteilung für Chemische Biologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany, ou_persistent22              
3Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, DE, ou_1950289              
4Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès (Bellaterra), Spain, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2012-09-232012-11-182012-11-262013-02-15
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/cb300505w
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Title: ACS Chemical Biology
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: 8 Volume / Issue: 8 (2) Sequence Number: - Start / End Page: 443 - 450 Identifier: ISSN: 1554-8929
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000035040