2021 journal article
Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase
Nature Communications.
MeSH headings : Acyltransferases / chemistry; Acyltransferases / genetics; Acyltransferases / metabolism; Catalytic Domain; Malonyl Coenzyme A; Molecular Dynamics Simulation; Mutagenesis; Polyketide Synthases / chemistry; Polyketide Synthases / genetics; Polyketide Synthases / metabolism; Polyketides; Protein Engineering; Secondary Metabolism; Substrate Specificity
TL;DR:
Molecular dynamics simulations are used to pinpoint mutations that impact AT domain selectivity and exchange structural motifs to obtain chimeric PKS modules with expanded substrate specificity, leading to identification of two previously unexplored structural motifS.
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open access via www.nature.com (publisher PDF)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science)
Source: ORCID
Added: April 14, 2021
AbstractPolyketides, 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.