{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:28:12Z","timestamp":1791192492093,"version":"4.1.0"},"reference-count":26,"publisher":"American Chemical Society (ACS)","issue":"11","license":[{"start":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T00:00:00Z","timestamp":1426118400000},"content-version":"vor","delay-in-days":10,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM076477"],"award-info":[{"award-number":["GM076477"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005496","name":"American Foundation for Pharmaceutical Education","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100005496","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006790","name":"College of Pharmacy, University of Michigan","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100006790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006801","name":"Horace H. Rackham School of Graduate Studies, University of Michigan","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100006801","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Biochemical characterization of polyketide synthases (PKSs) has relied on synthetic substrates functionalized as electrophilic esters to acylate the enzyme and initiate the catalytic cycle. In these efforts, N-acetylcysteamine thioesters have typically been employed for in vitro studies of full PKS modules as well as excised domains. However, substrate engineering approaches to control the catalytic cycle of a full PKS module harboring multiple domains remain underexplored. This study examines a series of alternatively activated native hexaketide substrates on the catalytic outcome of PikAIV, the sixth and final module of the pikromycin (Pik) pathway. We demonstrate the ability to control product formation with greater than 10:1 selectivity for either full module catalysis, leading to a 14-membered macrolactone, or direct cyclization to a 12-membered ring. This outcome was achieved through modifying the type of hexaketide ester employed, demonstrating the utility of substrate engineering in PKS functional studies and biocatalysis.<\/jats:p>","DOI":"10.1021\/ja511743n","type":"journal-article","created":{"date-parts":[[2015,3,2]],"date-time":"2015-03-02T17:56:56Z","timestamp":1425319016000},"page":"3735-3738","source":"Crossref","is-referenced-by-count":31,"title":["Substrate\nControlled Divergence in Polyketide Synthase\nCatalysis"],"prefix":"10.1021","volume":"137","author":[{"given":"Douglas A.","family":"Hansen","sequence":"first","affiliation":[{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron A.","family":"Koch","sequence":"additional","affiliation":[{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Sherman","sequence":"additional","affiliation":[{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,3,2]]},"reference":[{"key":"2026090304492779500_cit1a","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1021\/cr0503097","volume":"106","author":"Fischbach","year":"2006","journal-title":"Chem. 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Soc."},{"key":"2026090304492779500_cit5a","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/cbic.200900772","volume":"11","author":"Tosin","year":"2010","journal-title":"ChemBioChem"},{"key":"2026090304492779500_cit5b","doi-asserted-by":"crossref","first-page":"7079","DOI":"10.1002\/anie.200501670","volume":"44","author":"Spiteller","year":"2005","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090304492779500_cit6","doi-asserted-by":"crossref","first-page":"7557","DOI":"10.1002\/anie.200502246","volume":"44","author":"Wu","year":"2005","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090304492779500_cit7","doi-asserted-by":"crossref","first-page":"8441","DOI":"10.1021\/ja042592h","volume":"127","author":"Aldrich","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"2026090304492779500_cit8","unstructured":"Aldrich\n            ; et al.\n          (ref 7) monitored 10-dml (2) formation using Pik pentaketide (3) with PikAIII-TE\nand PikAIII\/PikAIV constructs, but not with Pik hexaketide (4) and PikAIV due to limitations of the assay employed."},{"key":"2026090304492779500_cit9","doi-asserted-by":"crossref","first-page":"5671","DOI":"10.1021\/ja034574q","volume":"125","author":"Yin","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"2026090304492779500_cit10","doi-asserted-by":"crossref","first-page":"11232","DOI":"10.1021\/ja404134f","volume":"135","author":"Hansen","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"2026090304492779500_cit11","doi-asserted-by":"crossref","first-page":"8910","DOI":"10.1021\/ja0504340","volume":"127","author":"Aldrich","year":"2005","journal-title":"J. Am. Chem. 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Chem.\nLett."},{"key":"2026090304492779500_cit15","doi-asserted-by":"crossref","first-page":"7171","DOI":"10.1016\/0040-4039(94)85352-5","volume":"35","author":"Evans","year":"1994","journal-title":"Tetrahedron Lett."},{"key":"2026090304492779500_cit16","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1016\/S0040-4039(01)00212-X","volume":"42","author":"Sawada","year":"2001","journal-title":"Tetrahedron\nLett."},{"key":"2026090304492779500_elcit921420643","first-page":"29","volume":"64","author":"Epp","year":"1998","journal-title":"J. Org. Chem."},{"key":"2026090304492779500_cit18","doi-asserted-by":"crossref","first-page":"11206","DOI":"10.1021\/ja9830290","volume":"120","author":"Pohl","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"2026090304492779500_cit19","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S1074-5521(03)00156-X","volume":"10","author":"Broadhurst","year":"2003","journal-title":"Chem. 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