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Rackham School of Graduate Studies, University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32-CA009676"],"award-info":[{"award-number":["T32-CA009676"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2020,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Engineering polyketide synthases (PKS) to produce new metabolites requires an understanding of catalytic points of failure during substrate processing. Growing evidence indicates the thioesterase (TE) domain as a significant bottleneck within engineered PKS systems. We created a series of hybrid PKS modules bearing exchanged TE domains from heterologous pathways and challenged them with both native and non\u2010native polyketide substrates. Reactions pairing wildtype PKS modules with non\u2010native substrates primarily resulted in poor conversions to anticipated macrolactones. Likewise, product formation with native substrates and hybrid PKS modules bearing non\u2010cognate TE domains was severely reduced. In contrast, non\u2010native substrates were converted by most hybrid modules containing a substrate compatible TE, directly implicating this domain as the major catalytic gatekeeper and highlighting its value as a target for protein engineering to improve analog production in PKS pathways.<\/jats:p>","DOI":"10.1002\/anie.202004991","type":"journal-article","created":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T19:45:30Z","timestamp":1588362330000},"page":"13575-13580","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases"],"prefix":"10.1002","volume":"59","author":[{"given":"Aaron A.","family":"Koch","sequence":"first","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Lowell","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"},{"name":"Current address: Department of Chemistry Virginia Tech  Blacksburg VA 24061 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.","family":"Coburn","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Chemler","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8334-3647","authenticated-orcid":false,"given":"David H.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Life Sciences Institute The University of Michigan (USA)  210 Washtenaw Avenue Ann Arbor MI 48109-2216 USA"},{"name":"Departments of Medicinal Chemistry, Chemistry, Microbiology &amp; 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