Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase

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dc.contributor.authorKalkreuter, Edwarden
dc.contributor.authorBingham, Kyle S.en
dc.contributor.authorKeeler, Aaron M.en
dc.contributor.authorLowell, Andrew N.en
dc.contributor.authorSchmidt, Jennifer J.en
dc.contributor.authorSherman, David H.en
dc.contributor.authorWilliams, Gavin J.en
dc.contributor.departmentChemistryen
dc.date.accessioned2021-08-13T17:12:30Zen
dc.date.available2021-08-13T17:12:30Zen
dc.date.issued2021-04-13en
dc.date.updated2021-08-13T17:12:27Zen
dc.description.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.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 2193 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41467-021-22497-2en
dc.identifier.eissn2041-1723en
dc.identifier.issn2041-1723en
dc.identifier.issue1en
dc.identifier.orcidLowell, Andrew [0000-0001-5357-5279]en
dc.identifier.other10.1038/s41467-021-22497-2 (PII)en
dc.identifier.pmid33850151 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/104639en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherNature Researchen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000640638000005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subject.meshMalonyl Coenzyme Aen
dc.subject.meshPolyketide Synthasesen
dc.subject.meshAcyltransferasesen
dc.subject.meshProtein Engineeringen
dc.subject.meshMutagenesisen
dc.subject.meshCatalytic Domainen
dc.subject.meshSubstrate Specificityen
dc.subject.meshMolecular Dynamics Simulationen
dc.subject.meshPolyketidesen
dc.subject.meshSecondary Metabolismen
dc.titleComputationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferaseen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2021-02-26en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/Chemistryen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen

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