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Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with <jats:italic>Escherichia coli<\/jats:italic> to manipulate <jats:italic>Micromonospora<\/jats:italic> for targeted gene\u2010replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A<jats:sub>1<\/jats:sub>, C, F, and H rings. Analyses of gene\u2010replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The <jats:italic>in\u2005vitro<\/jats:italic> activity of A<jats:sub>1<\/jats:sub>\u2010 and H\u2010ring\u2010modifying methyltransferases demonstrated the ability to catalyze late\u2010stage modification of the scaffold on an A<jats:sub>1<\/jats:sub>\u2010ring phenol and H\u2010ring C\u20104\u2019 hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and <jats:italic>in\u2005vitro<\/jats:italic> modification of advanced biosynthetic intermediates.<\/jats:p>","DOI":"10.1002\/cbic.202000305","type":"journal-article","created":{"date-parts":[[2020,7,19]],"date-time":"2020-07-19T22:16:16Z","timestamp":1595196976000},"page":"3349-3358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics and Analogues"],"prefix":"10.1002","volume":"21","author":[{"given":"Emilianne M.","family":"Limbrick","sequence":"first","affiliation":[{"name":"Department of Chemistry Vanderbilt University  7330 Stevenson Ctr Nashville TN 37235 USA"},{"name":"Department of Chemistry Mercer University  1501 Mercer University Drive Macon GA 31207 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey E.","family":"Y\u00f1igez\u2010Gutierrez","sequence":"additional","affiliation":[{"name":"Department of Chemistry Vanderbilt University  7330 Stevenson Ctr Nashville TN 37235 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callie C.","family":"Dulin","sequence":"additional","affiliation":[{"name":"Department of Chemistry Vanderbilt University  7330 Stevenson Ctr Nashville TN 37235 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmara K.","family":"Derewacz","sequence":"additional","affiliation":[{"name":"Department of Chemistry Vanderbilt University  7330 Stevenson Ctr Nashville TN 37235 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Spraggins","sequence":"additional","affiliation":[{"name":"Department of Chemistry Vanderbilt University  7330 Stevenson Ctr Nashville TN 37235 USA"},{"name":"Department of Biochemistry Vanderbilt University School of Medicine  607 Light Hall Nashville TN 37205 USA"},{"name":"Mass Spectrometry Research Center Vanderbilt University School of Medicine  465 21st Ave S Nashville TN 37240 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn M.","family":"McCulloch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Vanderbilt University 7124 MRBIII  465 21st Ave S Nashville TN 37232 USA"},{"name":"Department of Chemistry &amp; Biochemistry California State Polytechnic University, Pomona  3801 West Temple Ave Pomona CA 91768 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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