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  Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis

Bravo-Rodriguez, K., Klopries, S., Koopmans, K. R. M., Sundermann, U., Yahiaoui, S., Arens, J., et al. (2015). Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis. Chemistry & Biology, 22(11), 1425-1430. doi:10.1016/j.chembiol.2015.02.008.

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Bravo-Rodriguez, Kenny1, Author              
Klopries, Stephan2, Author
Koopmans, Kyra R. M.2, Author
Sundermann, Uschi3, Author
Yahiaoui, Samir4, Author
Arens, Julia2, Author
Kushnir, Susanna2, Author
Schulz, Frank2, Author
Sanchez Garcia, Elsa1, Author              
Affiliations:
1Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
2Fakultät für Chemie und Biochemie, Organische Chemie 1, Ruhr-Universität Bochum, Universitätsstraße 150, 44780 Bochum, Germany, ou_persistent22              
3Dr. Fooke-Achterrath Laboratorien GmbH, Habichtweg 16, 41468 Neuss, Germany, ou_persistent22              
4Université de Caen Basse-Normandie, Centre d’Etudes et de Recherche sur le Médicament de Normandie, 14032 Caen, France, ou_persistent22              

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 Abstract: Polyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme-substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification.

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Language(s): eng - English
 Dates: 2015-01-162014-10-222015-02-232015-10-292015-11-19
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.chembiol.2015.02.008
 Degree: -

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Title: Chemistry & Biology
  Other : Chem. Biol.
Source Genre: Journal
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Publ. Info: London : Cell Press
Pages: - Volume / Issue: 22 (11) Sequence Number: - Start / End Page: 1425 - 1430 Identifier: ISSN: 1074-5521
CoNE: https://pure.mpg.de/cone/journals/resource/954925604781