{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:37:09Z","timestamp":1792528629996,"version":"4.5.0"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"5","license":[{"start":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T00:00:00Z","timestamp":1425600000000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB-0948751"],"award-info":[{"award-number":["MCB-0948751"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI065357 RM DP 008"],"award-info":[{"award-number":["AI065357 RM DP 008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The phytotoxic fungal polyketides lasiodiplodin and resorcylide inhibit human blood coagulation factor XIIIa, mineralocorticoid receptors, and prostaglandin biosynthesis. These secondary metabolites belong to the 12-membered resorcylic acid lactone (RAL12) subclass of the benzenediol lactone (BDL) family. Identification of genomic loci for the biosynthesis of lasiodiplodin from Lasiodiplodia theobromae and resorcylide from Acremonium zeae revealed collaborating iterative polyketide synthase (iPKS) pairs whose efficient heterologous expression in Saccharomyces cerevisiae provided a convenient access to the RAL12 scaffolds desmethyl-lasiodiplodin and trans-resorcylide, respectively. Lasiodiplodin production was reconstituted in the heterologous host by co-expressing an O-methyltransferase also encoded in the lasiodiplodin cluster, while a glutathione-S-transferase was found not to be necessary for heterologous production. Clarification of the biogenesis of known resorcylide congeners in the heterologous host helped to disentangle the roles that biosynthetic irregularities and chemical interconversions play in generating chemical diversity. Observation of 14-membered RAL homologues during in vivo heterologous biosynthesis of RAL12 metabolites revealed \u201cstuttering\u201d by fungal iPKSs. The close global and domain-level sequence similarities of the orthologous BDL synthases across different structural subclasses implicate repeated horizontal gene transfers and\/or cluster losses in different fungal lineages. The absence of straightforward correlations between enzyme sequences and product structural features (the size of the macrocycle, the conformation of the exocyclic methyl group, or the extent of reduction by the hrPKS) suggest that BDL structural variety is the result of a select few mutations in key active site cavity positions.<\/jats:p>","DOI":"10.1021\/cb500043g","type":"journal-article","created":{"date-parts":[[2014,3,6]],"date-time":"2014-03-06T07:06:03Z","timestamp":1394089563000},"page":"1119-1127","source":"Crossref","is-referenced-by-count":65,"title":["Insights into the Biosynthesis of 12-Membered Resorcylic\nAcid Lactones from Heterologous Production in\n                    <i>Saccharomyces cerevisiae<\/i>"],"prefix":"10.1021","volume":"9","author":[{"given":"Yuquan","family":"Xu","sequence":"first","affiliation":[{"name":"Chinese Academy of Agricultural Sciences , , 12 Zhongguancun South St. , ,","place":["Beijing, People\u2019s Republic of China, 100081"]},{"name":"The University of Arizona , , 250 E. Valencia Rd. , , ,","place":["Tucson, Arizona, United States, 85706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Utah State University , , 4105 Old Main Hill , , ,","place":["Logan, Utah, United States, 84322"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Espinosa-Artiles","sequence":"additional","affiliation":[{"name":"The University of Arizona , , 250 E. Valencia Rd. , , ,","place":["Tucson, Arizona, United States, 85706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tang","sequence":"additional","affiliation":[{"name":"The University of Arizona , , 250 E. Valencia Rd. , , ,","place":["Tucson, Arizona, United States, 85706"]},{"name":"Sichuan University , , , ,","place":["Chengdu, Sichuan, People\u2019s Republic of China, 610064"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixun","family":"Zhan","sequence":"additional","affiliation":[{"name":"Utah State University , , 4105 Old Main Hill , , ,","place":["Logan, Utah, United States, 84322"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istva\u0301n","family":"Molna\u0301r","sequence":"additional","affiliation":[{"name":"The University of Arizona , , 250 E. Valencia Rd. , , ,","place":["Tucson, Arizona, United States, 85706"]},{"name":"The University of Arizona , , 1657 E. Helen St. , , ,","place":["Tucson, Arizona, United States, 85721"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,3,6]]},"reference":[{"key":"2026090120210877300_cit1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1039\/B610344H","article-title":"Chemistry\nand biology of resorcylic acid lactones","volume":"2007","author":"Winssinger","year":"2007","journal-title":"Chem.\nCommun."},{"key":"2026090120210877300_cit2","doi-asserted-by":"crossref","first-page":"5398","DOI":"10.1073\/pnas.1301201110","article-title":"Rational reprogramming\nof fungal\npolyketide first-ring cyclization","volume":"110","author":"Xu","year":"2013","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026090120210877300_cit3","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/1439-7633(20010903)2:9<612::AID-CBIC612>3.0.CO;2-Z","article-title":"A biosynthetic\nclassification of fungal and streptomycete fused-ring aromatic polyketides","volume":"2","author":"Thomas","year":"2001","journal-title":"ChemBioChem"},{"key":"2026090120210877300_cit4","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.2174\/156802609789895665","article-title":"Hsp90 inhibition with resorcyclic\nacid lactones (RALs)","volume":"9","author":"Winssinger","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"2026090120210877300_cit5","doi-asserted-by":"crossref","first-page":"4234","DOI":"10.1073\/pnas.0600445103","article-title":"Targeted\ncovalent inactivation of protein kinases by resorcylic acid lactone\npolyketides","volume":"103","author":"Schirmer","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090120210877300_cit6","doi-asserted-by":"crossref","first-page":"9933","DOI":"10.1021\/jo301592k","article-title":"Navigating the fungal\npolyketide chemical space: From genes to molecules","volume":"77","author":"Chooi","year":"2012","journal-title":"J. Org. Chem."},{"key":"2026090120210877300_cit7","doi-asserted-by":"crossref","first-page":"22764","DOI":"10.1074\/jbc.M110.128504","article-title":"Classification, prediction, and verification of the\nregioselectivity of fungal polyketide synthase product template domains","volume":"285","author":"Li","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090120210877300_cit8","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1038\/nature08475","article-title":"Structural basis\nfor biosynthetic programming of fungal aromatic polyketide cyclization","volume":"461","author":"Crawford","year":"2009","journal-title":"Nature"},{"key":"2026090120210877300_cit9","doi-asserted-by":"crossref","first-page":"6288","DOI":"10.1021\/bi9009049","article-title":"A thioesterase\nfrom an iterative fungal polyketide synthase shows macrocyclization\nand cross coupling activity and may play a role in controlling iterative\ncycling through product offloading","volume":"48","author":"Wang","year":"2009","journal-title":"Biochemistry"},{"key":"2026090120210877300_cit10","doi-asserted-by":"crossref","first-page":"10783","DOI":"10.1021\/ja4041362","article-title":"Thioesterase\ndomains of fungal nonreducing polyketide\nsynthases act as decision gates during combinatorial biosynthesis","volume":"135","author":"Xu","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"2026090120210877300_cit11","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1128\/AEM.72.3.1793-1799.2006","article-title":"Characterization of two polyketide synthase genes involved in zearalenone\nbiosynthesis in Gibberella zeae","volume":"72","author":"Gaffoor","year":"2006","journal-title":"Appl. Environ. Microbiol."},{"key":"2026090120210877300_cit12","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1016\/j.chembiol.2008.10.006","article-title":"Functional characterization of the\nbiosynthesis of radicicol, an Hsp90 inhibitor resorcylic acid lactone\nfrom Chaetomium chiversii","volume":"15","author":"Wang","year":"2008","journal-title":"Chem. Biol."},{"key":"2026090120210877300_cit13","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1128\/AEM.00478-08","article-title":"Genes for biosynthesis of the fungal\npolyketides hypothemycin from Hypomyces subiculosus and radicicol from Pochonia chlamydosporia","volume":"74","author":"Reeves","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"2026090120210877300_cit14","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1128\/AEM.03334-12","article-title":"Characterization of the biosynthetic genes for 10,11-dehydrocurvularin,\na heat-shock response modulator anticancer fungal polyketide from Aspergillus terreus","volume":"79","author":"Xu","year":"2013","journal-title":"Appl. Environ.\nMicrobiol."},{"key":"2026090120210877300_cit15","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1021\/ja100060k","article-title":"Enzymatic\nsynthesis of resorcylic acid lactones by cooperation of fungal iterative\npolyketide synthases involved in hypothemycin biosynthesis","volume":"132","author":"Zhou","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026090120210877300_cit16","doi-asserted-by":"crossref","first-page":"41412","DOI":"10.1074\/jbc.M110.183574","article-title":"Insights into\nradicicol biosynthesis via heterologous synthesis of intermediates\nand analogs","volume":"285","author":"Zhou","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090120210877300_cit17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0031-9422(00)00156-4","article-title":"Potato micro-tuber-inducing\nhydroxylasiodiplodins from Lasiodiplodia theobromae","volume":"54","author":"Yang","year":"2000","journal-title":"Phytochemistry"},{"key":"2026090120210877300_cit18","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1271\/bbb.69.1610","article-title":"Novel potato\nmicro-tuber-inducing compound, (3R,6S)-6-hydroxylasiodiplodin, from a strain of Lasiodiplodia theobromae","volume":"69","author":"Li","year":"2005","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"2026090120210877300_cit19","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.1021\/jf070082b","article-title":"Inhibition\nof photophosphorylation and electron transport chain in thylakoids\nby lasiodiplodin, a natural product from Botryosphaeria rhodina","volume":"55","author":"Veiga","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"2026090120210877300_cit20","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1007\/s12272-011-1205-x","article-title":"Cytotoxic lasiodiplodin\nderivatives\nfrom the fungus Syncephalastrum racemosum","volume":"34","author":"Buayairaksa","year":"2011","journal-title":"Arch. Pharmacal Res."},{"key":"2026090120210877300_cit21","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1248\/cpb.39.2956","article-title":"Biologically active\nconstituents of Arnebia euchroma: structure of arnebinol,\nan ansa-type monoterpenylbenzenoid with inhibitory activity on prostaglandin\nbiosynthesis","volume":"39","author":"Yao","year":"1991","journal-title":"Chem. Pharm. 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Chem."},{"key":"2026090120210877300_cit34","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/S0031-9422(98)00267-2","article-title":"Three lasiodiplodins from Lasiodiplodia theobromae IFO 31059","volume":"49","author":"Matsuura","year":"1998","journal-title":"Phytochemistry"},{"key":"2026090120210877300_cit35","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.str.2010.04.015","article-title":"Structural\nand functional analysis of A-type ketoreductases from the amphotericin\nmodular polyketide synthase","volume":"18","author":"Zheng","year":"2010","journal-title":"Structure"},{"key":"2026090120210877300_cit36","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1021\/np300653d","article-title":"Neocosmospora sp.-derived\nresorcylic acid lactones with in vitro binding affinity\nfor human opioid and cannabinoid receptors","volume":"76","author":"Gao","year":"2013","journal-title":"J. Nat. Prod."},{"key":"2026090120210877300_cit37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.bioorg.2007.11.002","article-title":"Starter unit specificity\ndirects genome mining of polyketide synthase pathways in fungi","volume":"36","author":"Crawford","year":"2008","journal-title":"Bioorg. Chem."},{"key":"2026090120210877300_cit38","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/cbic.200500430","article-title":"Broad substrate specificity of ketoreductases\nderived from modular polyketide synthases","volume":"7","author":"Bali","year":"2006","journal-title":"ChemBioChem"},{"key":"2026090120210877300_cit39","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1021\/ja3016395","article-title":"Illuminating the\ndiversity of aromatic polyketide synthases\nin Aspergillus nidulans","volume":"134","author":"Ahuja","year":"2012","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026090120210877300_cit40","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/S0031-9422(00)81811-7","article-title":"Minor metabolites of Monocillium nordinii","volume":"26","author":"Ayer","year":"1987","journal-title":"Phytochemistry"},{"key":"2026090120210877300_cit41","first-page":"169","article-title":"Action of an antiandrogen\non ontogenesis\nin the rat","volume":"114","author":"Galimberti","year":"1975","journal-title":"Boll. Chim. Farm."},{"key":"2026090120210877300_cit42","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1039\/b315020h","article-title":"Loss of co-linearity\nby modular polyketide\nsynthases: A mechanism for the evolution of chemical diversity","volume":"21","author":"Moss","year":"2004","journal-title":"Nat. Prod. Rep."},{"key":"2026090120210877300_cit43","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.chembiol.2003.11.009","article-title":"Iteration\nas programmed event during polyketide assembly;\nmolecular analysis of the aureothin biosynthesis gene cluster","volume":"10","author":"He","year":"2003","journal-title":"Chem. Biol."},{"key":"2026090120210877300_cit44","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.1128\/AAC.48.11.4120-4129.2004","article-title":"Chemical diversity of polyene macrolides\nproduced by Streptomyces noursei ATCC 11455 and recombinant\nstrain ERD44 with genetically altered polyketide synthase NysC","volume":"48","author":"Bruheim","year":"2004","journal-title":"Antimicrob. 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Biol."}],"container-title":["ACS Chemical\nBiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/cb500043g","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/5\/1119\/8527378\/cb500043g.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/5\/1119\/8527378\/cb500043g.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:21:21Z","timestamp":1788308481000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/9\/5\/1119\/823270\/Insights-into-the-Biosynthesis-of-12-Membered"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,6]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,3,6]]},"published-print":{"date-parts":[[2014,5,16]]}},"URL":"https:\/\/doi.org\/10.1021\/cb500043g","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,6]]}}}