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Here, we discover an unprecedented hydroxyl regioisomerization process in the biosynthesis of a rare carbon-4 deoxyanthracycline, which includes three tailoring steps performed by a four-enzyme cascade: two-component hydroxylases mediated a cryptic hydroxylation, and two NmrA-like short-chain dehydrogenase\/reductases catalyzed a reduction-dearomatization followed by a reduction-dehydration process. This study expands the enzymology and chemistry of type II polyketide synthase and provides tools to generate more analogs by engineering or enzymatic semisynthesis.<\/jats:p>","DOI":"10.1073\/pnas.1610097114","type":"journal-article","created":{"date-parts":[[2017,1,30]],"date-time":"2017-01-30T21:50:29Z","timestamp":1485813029000},"page":"1554-1559","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade"],"prefix":"10.1073","volume":"114","author":[{"given":"Zhuan","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Kang","family":"Gong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Min","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Biotechnology Research Center, Toyama Prefectural University, Toyama 939-0398, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-6288","authenticated-orcid":false,"given":"Lifeng","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong-Li","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,1,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1124\/pr.56.2.6","article-title":"Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity","volume":"56","author":"Minotti G","year":"2004","unstructured":"G Minotti, P Menna, E Salvatorelli, G Cairo, L Gianni, Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. 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