Nature Communications
| Autor: | Aaron M Keeler, Gavin J. Williams, Kyle S Bingham, David H. Sherman, Jennifer J. Schmidt, Edward Kalkreuter, Andrew N. Lowell |
|---|---|
| Přispěvatelé: | Chemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science General Physics and Astronomy Mutagenesis (molecular biology technique) Secondary Metabolism Computational biology Molecular dynamics Molecular Dynamics Simulation Protein Engineering 01 natural sciences General Biochemistry Genetics and Molecular Biology Article Substrate Specificity 03 medical and health sciences Polyketide Polyketide synthase Catalytic Domain Secondary metabolism Structural motif 030304 developmental biology Natural products 0303 health sciences Multidisciplinary biology 010405 organic chemistry Chemistry Active site Substrate (chemistry) General Chemistry Protein engineering Enzymes 0104 chemical sciences Malonyl Coenzyme A 030104 developmental biology Acyltransferases Mutagenesis Acyltransferase Polyketides biology.protein Natural product synthesis Selectivity Polyketide Synthases |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| Popis: | Polyketides, one of the largest classes of natural products, are often clinically relevant. The ability to engineer polyketide biosynthesis to produce analogs is critically important. Acyltransferases (ATs) of modular polyketide synthases (PKSs) catalyze the installation of malonyl-CoA extenders into polyketide scaffolds. ATs have been targeted extensively to site-selectively introduce various extenders into polyketides. Yet, a complete inventory of AT residues responsible for substrate selection has not been established, limiting the scope of AT engineering. Here, molecular dynamics simulations are used to prioritize ~50 mutations within the active site of EryAT6 from erythromycin biosynthesis, leading to identification of two previously unexplored structural motifs. Exchanging both motifs with those from ATs with alternative extender specificities provides chimeric PKS modules with expanded and inverted substrate specificity. Our enhanced understanding of AT substrate selectivity and application of this motif-swapping strategy are expected to advance our ability to engineer PKSs towards designer polyketides. Engineering efforts have focused on acyltransferase (AT) domains of modular polyketide synthases (PKSs) to site-selectively modify the resulting polyketides, but critical AT residues involved in substrate selection have not been fully elucidated. Here, the authors use molecular dynamics to pinpoint mutations that impact AT domain selectivity and exchange structural motifs to obtain chimeric PKS modules with expanded substrate specificity. |
| Databáze: | OpenAIRE |
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