Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis
| Autor: | Frank Schulz, Julia Arens, Samir Yahiaoui, Kyra R.M. Koopmans, Kenny Bravo-Rodriguez, Uschi Sundermann, Elsa Sanchez-Garcia, Susanna Kushnir, Stephan Klopries |
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| Rok vydání: | 2015 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Chemie Mutagenesis (molecular biology technique) Context (language use) Molecular Dynamics Simulation Biochemistry Substrate Specificity chemistry.chemical_compound Polyketide Biosynthesis Polyketide synthase Drug Discovery Molecular Biology Pharmacology biology Substrate (chemistry) General Medicine Anti-Bacterial Agents Erythromycin Protein Structure Tertiary chemistry Acyltransferases Acyltransferase Polyketides biology.protein Mutagenesis Site-Directed Molecular Medicine Biologie Polyketide Synthases |
| Zdroj: | Chemistry & Biology. 22(11):1425-1430 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2015.02.008 |
| Popis: | SummaryPolyketides 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. |
| Databáze: | OpenAIRE |
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